WorldWideScience

Sample records for human metabolic disease

  1. Human KATP channelopathies: diseases of metabolic homeostasis

    Science.gov (United States)

    2009-01-01

    Assembly of an inward rectifier K+ channel pore (Kir6.1/Kir6.2) and an adenosine triphosphate (ATP)-binding regulatory subunit (SUR1/SUR2A/SUR2B) forms ATP-sensitive K+ (KATP) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potential-dependent functions to match cellular energetic demands. Vital in the adaptive response to (patho)physiological stress, KATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in KATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in KATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, KATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation. A common Kir6.2 E23K polymorphism has been associated with late-onset diabetes and as a risk factor for maladaptive cardiac remodeling in the community-at-large and abnormal cardiopulmonary exercise stress performance in patients with heart failure. The overall mutation frequency within KATP channel genes and the spectrum of genotype–phenotype relationships remain to be established, while predicting consequences of a deficit in channel function is becoming increasingly feasible through systems biology approaches. Thus, advances in molecular medicine in the emerging field of human KATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy. PMID:20033705

  2. Assessing the human gut microbiota in metabolic diseases.

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    Karlsson, Fredrik; Tremaroli, Valentina; Nielsen, Jens; Bäckhed, Fredrik

    2013-10-01

    Recent findings have demonstrated that the gut microbiome complements our human genome with at least 100-fold more genes. In contrast to our Homo sapiens-derived genes, the microbiome is much more plastic, and its composition changes with age and diet, among other factors. An altered gut microbiota has been associated with several diseases, including obesity and diabetes, but the mechanisms involved remain elusive. Here we discuss factors that affect the gut microbiome, how the gut microbiome may contribute to metabolic diseases, and how to study the gut microbiome. Next-generation sequencing and development of software packages have led to the development of large-scale sequencing efforts to catalog the human microbiome. Furthermore, the use of genetically engineered gnotobiotic mouse models may increase our understanding of mechanisms by which the gut microbiome modulates host metabolism. A combination of classical microbiology, sequencing, and animal experiments may provide further insights into how the gut microbiota affect host metabolism and physiology.

  3. The implications of relationships between human diseases and metabolic subpathways.

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    Xia Li

    Full Text Available One of the challenging problems in the etiology of diseases is to explore the relationships between initiation and progression of diseases and abnormalities in local regions of metabolic pathways. To gain insight into such relationships, we applied the "k-clique" subpathway identification method to all disease-related gene sets. For each disease, the disease risk regions of metabolic pathways were then identified and considered as subpathways associated with the disease. We finally built a disease-metabolic subpathway network (DMSPN. Through analyses based on network biology, we found that a few subpathways, such as that of cytochrome P450, were highly connected with many diseases, and most belonged to fundamental metabolisms, suggesting that abnormalities of fundamental metabolic processes tend to cause more types of diseases. According to the categories of diseases and subpathways, we tested the clustering phenomenon of diseases and metabolic subpathways in the DMSPN. The results showed that both disease nodes and subpathway nodes displayed slight clustering phenomenon. We also tested correlations between network topology and genes within disease-related metabolic subpathways, and found that within a disease-related subpathway in the DMSPN, the ratio of disease genes and the ratio of tissue-specific genes significantly increased as the number of diseases caused by the subpathway increased. Surprisingly, the ratio of essential genes significantly decreased and the ratio of housekeeping genes remained relatively unchanged. Furthermore, the coexpression levels between disease genes and other types of genes were calculated for each subpathway in the DMSPN. The results indicated that those genes intensely influenced by disease genes, including essential genes and tissue-specific genes, might be significantly associated with the disease diversity of subpathways, suggesting that different kinds of genes within a disease-related subpathway may play

  4. The impact of metabolic disease associated with metabolic syndrome on human pregnancy.

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    Malek, Antoine

    2014-01-01

    Metabolic diseases induced by metabolic syndrome (MS) have been increased during the past two decades. During healthy pregnancy maternal organs and placenta are challenged to adapt to the increasingly physiological changes. In addition to the increasingly proatherogenic MS, pregnant woman develops a high cardiac output, hypercoagulability, increased inflammatory activity and insulin resistance with dyslipidemia. The MS describes a cluster of metabolic changes associated with an impact on the physiology of many organs. While the metabolic syndrome is directly responsible for the development of atherosclerotic cardiovascular disease, additional impact on human pregnancy like preterm delivery with low-birth-weight infants as well as the development of diseases such as diabetes, preeclampsia and hypertension. Recent evidence suggests that MS is originated in fetal life in association with maternal nutrition during pregnancy and fetal programming which apparently increases the susceptibility for MS in children and later life. This review will describe the MS in association with the origin of the emerging diseases during pregnancy such as diabetes, preeclampsia and others. The influence of perinatal environment and maternal diet and smoking on MS as well as the genetic biomarkers of MS will be described.

  5. Relevance of the Human Genome Project to inherited metabolic disease.

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    Burn, J

    1994-01-01

    The Human Genome Project is an international effort to identify the complete structure of the human genome. HUGO, the Human Genome Organization, facilitates international cooperation and exchange of information while the Genome Data Base will act as the on-line information retrieval and storage system for the huge amount of information being accumulated. The clinical register MIM (Mendelian Inheritance in Man) established by Victor McKusick is now an on-line resource that will allow biochemists working with inborn errors of metabolism to access the rapidly expanding body of knowledge. Biochemical and molecular genetics are complementary and should draw together to find solutions to the academic and clinical problems posed by inborn errors of metabolism.

  6. Mechanistic modeling of aberrant energy metabolism in human disease

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    Vineet eSangar

    2012-10-01

    Full Text Available Dysfunction in energy metabolism—including in pathways localized to the mitochondria—has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages—and also provides a powerful means to integrate and interpret—information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell.

  7. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

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    Pap, Attila; Cuaranta-Monroy, Ixchelt; Peloquin, Matthew; Nagy, Laszlo

    2016-01-01

    With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models—mainly mouse models—have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model. PMID:27483259

  8. Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease

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    Andrew Specht

    2011-01-01

    Full Text Available A canine model of Glycogen storage disease type Ia (GSDIa is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.

  9. Integrated analysis of transcript-level regulation of metabolism reveals disease-relevant nodes of the human metabolic network.

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    Galhardo, Mafalda; Sinkkonen, Lasse; Berninger, Philipp; Lin, Jake; Sauter, Thomas; Heinäniemi, Merja

    2014-02-01

    Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied through experimental and computational analysis. Integrating gene regulation data with a human metabolic network prompted the establishment of an open-sourced web portal, IDARE (Integrated Data Nodes of Regulation), for visualizing various gene-related data in context of metabolic pathways. Motivated by increasing availability of deep sequencing studies, we obtained ChIP-seq data from widely studied human umbilical vein endothelial cells. Interestingly, we found that association of metabolic genes with multiple transcription factors (TFs) enriched disease-associated genes. To demonstrate further extensions enabled by examining these networks together, constraint-based modeling was applied to data from human preadipocyte differentiation. In parallel, data on gene expression, genome-wide ChIP-seq profiles for peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer binding protein (CEBP) α, liver X receptor (LXR) and H3K4me3 and microRNA target identification for miR-27a, miR-29a and miR-222 were collected. Disease-relevant key nodes, including mitochondrial glycerol-3-phosphate acyltransferase (GPAM), were exposed from metabolic pathways predicted to change activity by focusing on association with multiple regulators. In both cell types, our analysis reveals the convergence of microRNAs and TFs within the branched chain amino acid (BCAA) metabolic pathway, possibly providing an explanation for its downregulation in obese and diabetic conditions.

  10. Systems biology from micro-organisms to human metabolic diseases: the role of detailed kinetic models.

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    Bakker, Barbara M; van Eunen, Karen; Jeneson, Jeroen A L; van Riel, Natal A W; Bruggeman, Frank J; Teusink, Bas

    2010-10-01

    Human metabolic diseases are typically network diseases. This holds not only for multifactorial diseases, such as metabolic syndrome or Type 2 diabetes, but even when a single gene defect is the primary cause, where the adaptive response of the entire network determines the severity of disease. The latter may differ between individuals carrying the same mutation. Understanding the adaptive responses of human metabolism naturally requires a systems biology approach. Modelling of metabolic pathways in micro-organisms and some mammalian tissues has yielded many insights, qualitative as well as quantitative, into their control and regulation. Yet, even for a well-known pathway such as glycolysis, precise predictions of metabolite dynamics from experimentally determined enzyme kinetics have been only moderately successful. In the present review, we compare kinetic models of glycolysis in three cell types (African trypanosomes, yeast and skeletal muscle), evaluate their predictive power and identify limitations in our understanding. Although each of these models has its own merits and shortcomings, they also share common features. For example, in each case independently measured enzyme kinetic parameters were used as input. Based on these 'lessons from glycolysis', we will discuss how to make best use of kinetic computer models to advance our understanding of human metabolic diseases.

  11. Developmental origins of health and disease: experimental and human evidence of fetal programming for metabolic syndrome.

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    de Gusmão Correia, M L; Volpato, A M; Águila, M B; Mandarim-de-Lacerda, C A

    2012-07-01

    The concept of developmental origins of health and disease has been defined as the process through which the environment encountered before birth, or in infancy, shapes the long-term control of tissue physiology and homeostasis. The evidence for programming derives from a large number of experimental and epidemiological observations. Several nutritional interventions during diverse phases of pregnancy and lactation in rodents are associated with fetal and neonatal programming for metabolic syndrome. In this paper, recent experimental models and human epidemiological studies providing evidence for the fetal programming associated with the development of metabolic syndrome and related diseases are revisited.

  12. Effect of maternal diet on the epigenome: implications for human metabolic disease.

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    Lillycrop, Karen A

    2011-02-01

    The rapid increase in the incidence of chronic non-communicable diseases over the past two decades cannot be explained solely by genetic and adult lifestyle factors. There is now considerable evidence that the fetal and early postnatal environment also strongly influences the risk of developing such diseases in later life. Human studies have shown that low birth weight is associated with an increased risk of CVD, type II diabetes, obesity and hypertension, although recent studies have shown that over-nutrition in early life can also increase susceptibility to future metabolic disease. These findings have been replicated in a variety of animal models, which have shown that both maternal under- and over-nutrition can induce persistent changes in gene expression and metabolism within the offspring. The mechanism by which the maternal nutritional environment induces such changes is beginning to be understood and involves the altered epigenetic regulation of specific genes. The demonstration of a role for altered epigenetic regulation of genes in the developmental induction of chronic diseases raises the possibility that nutritional or pharmaceutical interventions may be used to modify long-term cardio-metabolic disease risk and combat this rapid rise in chronic non-communicable diseases.

  13. Strain-level dissection of the contribution of the gut microbiome to human metabolic disease.

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    Zhang, Chenhong; Zhao, Liping

    2016-04-20

    The gut microbiota has been linked with metabolic diseases in humans, but demonstration of causality remains a challenge. The gut microbiota, as a complex microbial ecosystem, consists of hundreds of individual bacterial species, each of which contains many strains with high genetic diversity. Recent advances in genomic and metabolomic technologies are facilitating strain-level dissection of the contribution of the gut microbiome to metabolic diseases. Interventional studies and correlation analysis between variations in the microbiome and metabolome, captured by longitudinal sampling, can lead to the identification of specific bacterial strains that may contribute to human metabolic diseases via the production of bioactive metabolites. For example, high-quality draft genomes of prevalent gut bacterial strains can be assembled directly from metagenomic datasets using a canopy-based algorithm. Specific metabolites associated with a disease phenotype can be identified by nuclear magnetic resonance-based metabolomics of urine and other samples. Such multi-omics approaches can be employed to identify specific gut bacterial genomes that are not only correlated with detected metabolites but also encode the genes required for producing the precursors of those metabolites in the gut. Here, we argue that if a causative role can be demonstrated in follow-up mechanistic studies--for example, using gnotobiotic models--such functional strains have the potential to become biomarkers for diagnostics and targets for therapeutics.

  14. Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases.

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    Shekhawat, Prem; Bennett, Michael J; Sadovsky, Yoel; Nelson, D Michael; Rakheja, Dinesh; Strauss, Arnold W

    2003-06-01

    The role of fat metabolism during human pregnancy and in placental growth and function is poorly understood. Mitochondrial fatty acid oxidation disorders in an affected fetus are associated with maternal diseases of pregnancy, including preeclampsia, acute fatty liver of pregnancy, and the hemolysis, elevated liver enzymes, and low platelets syndrome called HELLP. We have investigated the developmental expression and activity of six fatty acid beta-oxidation enzymes at various gestational-age human placentas. Placental specimens exhibited abundant expression of all six enzymes, as assessed by immunohistochemical and immunoblot analyses, with greater staining in syncytiotrophoblasts compared with other placental cell types. beta-Oxidation enzyme activities in placental tissues were higher early in gestation and lower near term. Trophoblast cells in culture oxidized tritium-labeled palmitate and myristate in substantial amounts, indicating that the human placenta utilizes fatty acids as a significant metabolic fuel. Thus human placenta derives energy from fatty acid oxidation, providing a potential explanation for the association of fetal fatty acid oxidation disorders with maternal liver diseases in pregnancy.

  15. Explanted diseased livers - a possible source of metabolic competent primary human hepatocytes.

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    Kleine, Moritz; Riemer, Marc; Krech, Till; DeTemple, Daphne; Jäger, Mark D; Lehner, Frank; Manns, Michael P; Klempnauer, Jürgen; Borlak, Jürgen; Bektas, Hueseyin; Vondran, Florian W R

    2014-01-01

    Being an integral part of basic, translational and clinical research, the demand for primary human hepatocytes (PHH) is continuously growing while the availability of tissue resection material for the isolation of metabolically competent PHH remains limited. To overcome current shortcomings, this study evaluated the use of explanted diseased organs from liver transplantation patients as a potential source of PHH. Therefore, PHH were isolated from resected surgical specimens (Rx-group; n = 60) and explanted diseased livers obtained from graft recipients with low labMELD-score (Ex-group; n = 5). Using established protocols PHH were subsequently cultured for a period of 7 days. The viability and metabolic competence of cultured PHH was assessed by the following parameters: morphology and cell count (CyQuant assay), albumin synthesis, urea production, AST-leakage, and phase I and II metabolism. Both groups were compared in terms of cell yield and metabolic function, and results were correlated with clinical parameters of tissue donors. Notably, cellular yields and viabilities were comparable between the Rx- and Ex-group and were 5.3±0.5 and 2.9±0.7×106 cells/g liver tissue with 84.3±1.3 and 76.0±8.6% viability, respectively. Moreover, PHH isolated from the Rx- or Ex-group did not differ in regards to loss of cell number in culture, albumin synthesis, urea production, AST-leakage, and phase I and II metabolism (measured by the 7-ethoxycoumarin-O-deethylase and uracil-5'-diphosphate-glucuronyltransferase activity). Likewise, basal transcript expressions of the CYP monooxygenases 1A1, 2C8 and 3A4 were comparable as was their induction when treated with a cocktail that consisted of 3-methylcholantren, rifampicin and phenobarbital, with increased expression of CYP 1A1 and 3A4 mRNA while transcript expression of CYP 2C8 was only marginally changed. In conclusion, the use of explanted diseased livers obtained from recipients with low labMELD-score might represent

  16. Diet-gene interactions and PUFA metabolism: a potential contributor to health disparities and human diseases.

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    Chilton, Floyd H; Murphy, Robert C; Wilson, Bryan A; Sergeant, Susan; Ainsworth, Hannah; Seeds, Michael C; Mathias, Rasika A

    2014-05-21

    The "modern western" diet (MWD) has increased the onset and progression of chronic human diseases as qualitatively and quantitatively maladaptive dietary components give rise to obesity and destructive gene-diet interactions. There has been a three-fold increase in dietary levels of the omega-6 (n-6) 18 carbon (C18), polyunsaturated fatty acid (PUFA) linoleic acid (LA; 18:2n-6), with the addition of cooking oils and processed foods to the MWD. Intense debate has emerged regarding the impact of this increase on human health. Recent studies have uncovered population-related genetic variation in the LCPUFA biosynthetic pathway (especially within the fatty acid desaturase gene (FADS) cluster) that is associated with levels of circulating and tissue PUFAs and several biomarkers and clinical endpoints of cardiovascular disease (CVD). Importantly, populations of African descent have higher frequencies of variants associated with elevated levels of arachidonic acid (ARA), CVD biomarkers and disease endpoints. Additionally, nutrigenomic interactions between dietary n-6 PUFAs and variants in genes that encode for enzymes that mobilize and metabolize ARA to eicosanoids have been identified. These observations raise important questions of whether gene-PUFA interactions are differentially driving the risk of cardiovascular and other diseases in diverse populations, and contributing to health disparities, especially in African American populations.

  17. Diet-Gene Interactions and PUFA Metabolism: A Potential Contributor to Health Disparities and Human Diseases

    Directory of Open Access Journals (Sweden)

    Floyd H. Chilton

    2014-05-01

    Full Text Available The “modern western” diet (MWD has increased the onset and progression of chronic human diseases as qualitatively and quantitatively maladaptive dietary components give rise to obesity and destructive gene-diet interactions. There has been a three-fold increase in dietary levels of the omega-6 (n-6 18 carbon (C18, polyunsaturated fatty acid (PUFA linoleic acid (LA; 18:2n-6, with the addition of cooking oils and processed foods to the MWD. Intense debate has emerged regarding the impact of this increase on human health. Recent studies have uncovered population-related genetic variation in the LCPUFA biosynthetic pathway (especially within the fatty acid desaturase gene (FADS cluster that is associated with levels of circulating and tissue PUFAs and several biomarkers and clinical endpoints of cardiovascular disease (CVD. Importantly, populations of African descent have higher frequencies of variants associated with elevated levels of arachidonic acid (ARA, CVD biomarkers and disease endpoints. Additionally, nutrigenomic interactions between dietary n-6 PUFAs and variants in genes that encode for enzymes that mobilize and metabolize ARA to eicosanoids have been identified. These observations raise important questions of whether gene-PUFA interactions are differentially driving the risk of cardiovascular and other diseases in diverse populations, and contributing to health disparities, especially in African American populations.

  18. [Consensus statement: recommendations for the management of metabolic bone disease in human immunodeficiency virus patients].

    Science.gov (United States)

    Martínez, Esteban; Jódar Gimeno, Esteban; Reyes García, Rebeca; Carpintero, Pedro; Casado, José Luis; Del Pino Montes, Javier; Domingo Pedrol, Pere; Estrada, Vicente; Maalouf, Jorge; Negredo, Eugenia; Ocampo, Antonio; Muñoz-Torres, Manuel

    2014-04-01

    To provide practical recommendations for the evaluation and treatment of metabolic bone disease in human immunodeficiency virus (HIV) patients. Members of scientific societies related to bone metabolism and HIV: Grupo de Estudio de Sida (GeSIDA), Sociedad Española de Endocrinología y Nutrición (SEEN), Sociedad Española de Investigación Ósea y del Metabolismo Mineral (SEIOMM), and Sociedad Española de Fractura Osteoporótica (SEFRAOS). A systematic search was carried out in PubMed, and papers in English and Spanish with a publication date before 28 May 2013 were included. Recommendations were formulated according to GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) setting both their strength and the quality of supporting evidence. Working groups were established for each major part, and the final resulting document was later discussed in a face-to-face meeting. All the authors reviewed the final written document and agreed with its content. The document provides evidence-based practical recommendations on the detection and treatment of bone disease in HIV-infected patients. Copyright © 2013 Elsevier España, S.L. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  19. Impact of weight regain on metabolic disease risk: a review of human trials.

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    Kroeger, Cynthia M; Hoddy, Kristin K; Varady, Krista A

    2014-01-01

    Dietary restriction interventions are effective for weight loss and reduction of chronic disease risk. Unfortunately, most people tend to regain much of this lost weight within one year after intervention. While some studies suggest that minor degrees of weight regain have no effect on metabolic disease risk parameters, other studies demonstrate a complete reversal in metabolic benefits. In light of these conflicting findings, it is of interest to determine how complete weight maintenance versus mild weight regain affects key risk parameters. These findings would have important clinical implications, as they could help identify a weight regain threshold that could preserve the metabolic benefits of weight loss. Accordingly, this review examined the impact of no weight regain versus mild regain on various metabolic disease risk parameters, including plasma lipids, blood pressure, glucose, and insulin concentrations, in adult subjects.

  20. Impact of Weight Regain on Metabolic Disease Risk: A Review of Human Trials

    Directory of Open Access Journals (Sweden)

    Cynthia M. Kroeger

    2014-01-01

    Full Text Available Dietary restriction interventions are effective for weight loss and reduction of chronic disease risk. Unfortunately, most people tend to regain much of this lost weight within one year after intervention. While some studies suggest that minor degrees of weight regain have no effect on metabolic disease risk parameters, other studies demonstrate a complete reversal in metabolic benefits. In light of these conflicting findings, it is of interest to determine how complete weight maintenance versus mild weight regain affects key risk parameters. These findings would have important clinical implications, as they could help identify a weight regain threshold that could preserve the metabolic benefits of weight loss. Accordingly, this review examined the impact of no weight regain versus mild regain on various metabolic disease risk parameters, including plasma lipids, blood pressure, glucose, and insulin concentrations, in adult subjects.

  1. Activation of IRF1 in Human Adipocytes Leads to Phenotypes Associated with Metabolic Disease.

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    Friesen, Max; Camahort, Raymond; Lee, Youn-Kyoung; Xia, Fang; Gerszten, Robert E; Rhee, Eugene P; Deo, Rahul C; Cowan, Chad A

    2017-05-09

    The striking rise of obesity-related metabolic disorders has focused attention on adipocytes as critical mediators of disease phenotypes. To better understand the role played by excess adipose in metabolic dysfunction it is crucial to decipher the transcriptional underpinnings of the low-grade adipose inflammation characteristic of diseases such as type 2 diabetes. Through employing a comparative transcriptomics approach, we identified IRF1 as differentially regulated between primary and in vitro-derived genetically matched adipocytes. This suggests a role as a mediator of adipocyte inflammatory phenotypes, similar to its function in other tissues. Utilizing adipose-derived mesenchymal progenitors we subsequently demonstrated that expression of IRF1 in adipocytes indeed contributes to upregulation of inflammatory processes, both in vitro and in vivo. This highlights IRF1's relevance to obesity-related inflammation and the resultant metabolic dysregulation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardiovascular disease?

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    Chaldakov, George N; Fiore, Marco; Stankulov, Ivan S; Manni, Luigi; Hristova, Mariyana G; Antonelli, Alessia; Ghenev, Peter I; Aloe, Luigi

    2004-01-01

    The development of atherosclerotic cardiovascular disease is a common comorbidity in patients with the metabolic syndrome, a concurrence of cardiovascular risk factors in one individual. While multiple growth factors and adipokines are identified in atherosclerotic lesions, as well as neurotrophins implicated in both cardiac ischemia and lipid and glucose metabolism, the potential role of neurotrophins in human coronary atherosclerosis and in the metabolic syndrome still remains to be elucidated. Here we describe and discuss our results that represent a novel attempt to study the cardiovascular and metabolic biology of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and mast cells (MC). The local amount of NGF, the immunolocalization of p75 neurotrophin receptor (p75NTR) and the number of MC were correlatively examined in coronary vascular wall and in the surrounding subepicardial adipose tissue, obtained from autopsy cases in humans with advanced coronary atherosclerosis. We also analyzed the plasma levels of NGF, BDNF and leptin and the number of MC in biopsies from abdominal subcutaneous adipose tissue in patients with a severe form of the metabolic syndrome. The results demonstrate that NGF levels are decreased in atherosclerotic coronary vascular tissue but increased in the subepicardial adipose tissue, whereas both tissues express a greater number of MC and a stronger p75NTR immunoreactivity, compared to controls. Metabolic syndrome patients display a significant hyponeurotrophinemia and an increased number of adipose MC; the later correlates with elevated plasma leptin levels. In effect, we provide the first evidence for (i) an altered presence of NGF, p75NTR and MC in both coronary vascular and subepicardial adipose tissue in human coronary atherosclerosis, and (ii) a significant decrease in plasma NGF and BDNF levels and an elevated amount of plasma leptin and adipose MC in metabolic syndrome patients. Together our findings suggest that

  3. The Use of Signal-Transduction and Metabolic Pathways to Predict Human Disease Targets from Electric and Magnetic Fields Using in vitro Data in Human Cell Lines

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    Parham, Fred; Portier, Christopher J.; Chang, Xiaoqing; Mevissen, Meike

    2016-01-01

    Using in vitro data in human cell lines, several research groups have investigated changes in gene expression in cellular systems following exposure to extremely low frequency (ELF) and radiofrequency (RF) electromagnetic fields (EMF). For ELF EMF, we obtained five studies with complete microarray data and three studies with only lists of significantly altered genes. Likewise, for RF EMF, we obtained 13 complete microarray datasets and 5 limited datasets. Plausible linkages between exposure to ELF and RF EMF and human diseases were identified using a three-step process: (a) linking genes associated with classes of human diseases to molecular pathways, (b) linking pathways to ELF and RF EMF microarray data, and (c) identifying associations between human disease and EMF exposures where the pathways are significantly similar. A total of 60 pathways were associated with human diseases, mostly focused on basic cellular functions like JAK–STAT signaling or metabolic functions like xenobiotic metabolism by cytochrome P450 enzymes. ELF EMF datasets were sporadically linked to human diseases, but no clear pattern emerged. Individual datasets showed some linkage to cancer, chemical dependency, metabolic disorders, and neurological disorders. RF EMF datasets were not strongly linked to any disorders but strongly linked to changes in several pathways. Based on these analyses, the most promising area for further research would be to focus on EMF and neurological function and disorders. PMID:27656641

  4. Biconnectivity of the cellular metabolism: A cross-species study and its implication for human diseases

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    Kim, P.; Lee, D.-S.; Kahng, B.

    2015-01-01

    The maintenance of stability during perturbations is essential for living organisms, and cellular networks organize multiple pathways to enable elements to remain connected and communicate, even when some pathways are broken. Here, we evaluated the biconnectivity of the metabolic networks of 506 species in terms of the clustering coefficients and the largest biconnected components (LBCs), wherein a biconnected component (BC) indicates a set of nodes in which every pair is connected by more than one path. Via comparison with the rewired networks, we illustrated how biconnectivity in cellular metabolism is achieved on small and large scales. Defining the biconnectivity of individual metabolic compounds by counting the number of species in which the compound belonged to the LBC, we demonstrated that biconnectivity is significantly correlated with the evolutionary age and functional importance of a compound. The prevalence of diseases associated with each metabolic compound quantifies the compounds vulnerability, i.e., the likelihood that it will cause a metabolic disorder. Moreover, the vulnerability depends on both the biconnectivity and the lethality of the compound. This fact can be used in drug discovery and medical treatments. PMID:26490723

  5. In Vitro Disease Model of Microgravity Conditioning on Human Energy Metabolism

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    Snyder, Jessica; Culbertson, C.; Zhang, Ye; Emami, K.; Wu, H.; Sun, Wei

    2010-01-01

    NASA and its partners are committed to introducing appropriate new technology to enable learning and living safely beyond the Earth for extended periods of time in a sustainable and possibly indefinite manner. In the responsible acquisition of that goal, life sciences is tasked to tune and advance current medical technology to prepare for human health and wellness in the space environment. The space environment affects the condition and function of biological systems from organ level function to shape of individual organelles. The objective of this paper is to study the effect of microgravity on kinetics of drug metabolism. This fundamental characterization is meaningful to (1) scientific understanding of the response of biology to microgravity and (2) clinical dosing requirements and pharmacological thresholds during long term manned space exploration. Metabolism kinetics of the anti-nausea drug promethazine (PMZ) were determined by an in vitro ground model of 3-dimensional aggregates of human hepatocytes conditioned to weightlessness using a rotating wall bioreactor. The authors observed up-regulated PMZ conversion in model microgravity conditions and attribute this to effect to model microgravity conditioning acting on metabolic mechanisms of the cells. Further work is necessary to determine which particular cellular mechanisms are governing the experimental observations, but the authors conclude kinetics of drug metabolism are responsive to gravitational fields and further study of this sensitivity would improve dosing of pharmaceuticals to persons exposed to a microgravity environment.

  6. Metabolic disease network and its implication for disease comorbidity

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    Lee, Deok-Sun; Oltvai, Zoltan; Christakis, Nicholas; Barabasi, Albert-Laszlo

    2008-03-01

    Given that most diseases are the result of the breakdown of some cellular processes, a key aim of modern medicine is to establish the relationship between disease phenotypes and the various disruptions in the underlying cellular networks. Here we show that our current understanding of the structure of the human metabolic network can provide insight into potential relationships among often distinct disease phenotypes. Using the known enzyme-disease associations, we construct a human metabolic disease network in which nodes are diseases and two diseases are linked if the enzymes associated with them catalyze adjacent metabolic reactions. We find that the more connected a disease is, the higher is its prevalence and the chance that it is associated with a high mortality. The results indicate that the cellular network-level relationships between metabolic pathways and the associated disease provide insights into disease comorbidity, with potential important consequences on disease diagnosis and prevention.

  7. Cholesterol metabolism in Huntington disease.

    Science.gov (United States)

    Karasinska, Joanna M; Hayden, Michael R

    2011-09-06

    The CNS is rich in cholesterol, which is essential for neuronal development and survival, synapse maturation, and optimal synaptic activity. Alterations in brain cholesterol homeostasis are linked to neurodegeneration. Studies have demonstrated that Huntington disease (HD), a progressive and fatal neurodegenerative disorder resulting from polyglutamine expansion in the huntingtin protein, is associated with changes in cellular cholesterol metabolism. Emerging evidence from human and animal studies indicates that attenuated brain sterol synthesis and accumulation of cholesterol in neuronal membranes represent two distinct mechanisms occurring in the presence of mutant huntingtin that influence neuronal survival. Increased knowledge of how changes in intraneuronal cholesterol metabolism influence the pathogenesis of HD will provide insights into the potential application of brain cholesterol regulation as a therapeutic strategy for this devastating disease.

  8. Systematic analysis of transcription-level effects of neurodegenerative diseases on human brain metabolism by a newly reconstructed brain-specific metabolic network

    Directory of Open Access Journals (Sweden)

    Mustafa Sertbaş

    2014-01-01

    Full Text Available Network-oriented analysis is essential to identify those parts of a cell affected by a given perturbation. The effect of neurodegenerative perturbations in the form of diseases of brain metabolism was investigated by using a newly reconstructed brain-specific metabolic network. The developed stoichiometric model correctly represents healthy brain metabolism, and includes 630 metabolic reactions in and between astrocytes and neurons, which are controlled by 570 genes. The integration of transcriptome data of six neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia with the model was performed to identify reporter features specific and common for these diseases, which revealed metabolites and pathways around which the most significant changes occur. The identified metabolites are potential biomarkers for the pathology of the related diseases. Our model indicated perturbations in oxidative stress, energy metabolism including TCA cycle and lipid metabolism as well as several amino acid related pathways, in agreement with the role of these pathways in the studied diseases. The computational prediction of transcription factors that commonly regulate the reporter metabolites was achieved through binding-site analysis. Literature support for the identified transcription factors such as USF1, SP1 and those from FOX families are known from the literature to have regulatory roles in the identified reporter metabolic pathways as well as in the neurodegenerative diseases. In essence, the reconstructed brain model enables the elucidation of effects of a perturbation on brain metabolism and the illumination of possible machineries in which a specific metabolite or pathway acts as a regulatory spot for cellular reorganization.

  9. Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington's Disease human lymphoblasts.

    Science.gov (United States)

    Naia, Luana; Ferreira, I Luísa; Cunha-Oliveira, Teresa; Duarte, Ana I; Ribeiro, Márcio; Rosenstock, Tatiana R; Laço, Mário N; Ribeiro, Maria J; Oliveira, Catarina R; Saudou, Frédéric; Humbert, Sandrine; Rego, A Cristina

    2015-02-01

    Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca(2+) levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca(2+) accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.

  10. Role of CCK/gastrin receptors in gastrointestinal/metabolic diseases and results of human studies using gastrin/CCK receptor agonists/antagonists in these diseases

    Science.gov (United States)

    Berna, Marc J.; Jensen, Robert T.

    2009-01-01

    In this paper, the estabished and possible roles of CCK1 and CCK2 receptors in gastrointestinal (GI) and metabolic diseases are reviewed and available results from human agonist/antagonist studies are discussed. While there is evidence for the involvement of CCK1R in numerous diseases including pancreatic disorders, motility disorders, tumor growth, regulation of satiety and a number of CCK-deficient states, the role of CCK1R in these conditions is not clearly defined. There are encouraging data from several clinical studies of CCK1R antagonists in some of these conditions, but their role as therapeutic agents remains unclear. The role of CCK2R in physiological (atrophic gastritis, pernicious anemia) and pathological (Zollinger-Ellison syndrome) hypergastrinemic states, its effects on the gastric mucosa (ECL cell hyperplasia, carcinoids, parietal cell mass) and its role in acid-peptic disorders are clearly defined. Furthermore, recent studies point to a possible role for CCK2R in a number of GI malignancies. Current data from human studies of CCK2R antagonists are presented and their potential role in the treatment of these conditions reviewed. Furthermore, the role of CCK2 receptors as targets for medical imaging is discussed. Even though cholecystokinin (CCK) and gastrin were among the first gastrointestinal hormones discovered [1,2], both their physiological roles as well as their roles in clinically relevant gastrointestinal diseases remain unclear and even controversial in many cases [3–6]. The structural characterization of CCK and gastrin [7,8], pharmacological identification [9–13] and cloning [14,15] of CCK and gastrin receptors (CCK1R, CCK2R), characterization of receptor location, peptide and receptor genes, development of receptor antagonists and receptor/agonist knockout animals [16–21] have led to important advancements in our understanding of the physiological and pathophysiological role of CCK and gastrin signaling [3]. Most of these topics

  11. Metabolic syndrome and eye diseases.

    Science.gov (United States)

    Poh, Stanley; Mohamed Abdul, Riswana Banu Binte; Lamoureux, Ecosse L; Wong, Tien Y; Sabanayagam, Charumathi

    2016-03-01

    Metabolic syndrome is becoming a worldwide medical and public health challenge as it has been seen increasing in prevalence over the years. Age-related eye diseases, the leading cause of blindness globally and visual impairment in developed countries, are also on the rise due to aging of the population. Many of the individual components of the metabolic syndrome have been shown to be associated with these eye diseases. However, the association of metabolic syndrome with eye diseases is not clear. In this review, we reviewed the evidence for associations between metabolic syndrome and certain ocular diseases in populations. We also reviewed the association of individual metabolic syndrome components with ocular diseases due to a paucity of research in this area. Besides, we also summarised the current understanding of etiological mechanisms of how metabolic syndrome or the individual components lead to these ocular diseases. With increasing evidence of such associations, it may be important to identify patients who are at risk of developing metabolic syndrome as prompt treatment and intervention may potentially decrease the risk of developing certain ocular diseases.

  12. Martial Arts and Metabolic Diseases

    Directory of Open Access Journals (Sweden)

    Hidetaka Hamasaki

    2016-05-01

    Full Text Available Different forms of martial arts are practiced worldwide, each with various intensities of physical activity. These disciplines are potentially an effective exercise therapy for metabolic diseases. Tai chi is the most well-studied style of martial arts and has shown evidence of its effect on metabolic diseases; however, little evidence is available regarding the association between other styles of martial arts and metabolic health. To summarize and evaluate the effects of martial arts on metabolic diseases, eligible articles were searched by using Pubmed. To date, systematic reviews provide no definite conclusion on the effectiveness of tai chi for treating metabolic diseases because of a small numbers of subjects, short durations of clinical trials, and some biases involved in testing. However, there are several clinical studies on subjects with metabolic diseases, which show that tai chi improves obesity, glycemic control, blood pressure control, and lipid profiles. Currently, some limited evidence suggests that other martial arts, such as kung fu and karate, may be beneficial for body composition, glycemic control, and arterial stiffness. To clarify the effectiveness of martial arts for treating metabolic diseases, well-designed prospective studies, preferably with a larger number of subjects and of longer duration, are warranted.

  13. Lysophosphatidylinositol Signalling and Metabolic Diseases

    Directory of Open Access Journals (Sweden)

    Syamsul A. Arifin

    2016-01-01

    Full Text Available Metabolism is a chemical process used by cells to transform food-derived nutrients, such as proteins, carbohydrates and fats, into chemical and thermal energy. Whenever an alteration of this process occurs, the chemical balance within the cells is impaired and this can affect their growth and response to the environment, leading to the development of a metabolic disease. Metabolic syndrome, a cluster of several metabolic risk factors such as abdominal obesity, insulin resistance, high cholesterol and high blood pressure, and atherogenic dyslipidaemia, is increasingly common in modern society. Metabolic syndrome, as well as other diseases, such as diabetes, obesity, hyperlipidaemia and hypertension, are associated with abnormal lipid metabolism. Cellular lipids are the major component of cell membranes; they represent also a valuable source of energy and therefore play a crucial role for both cellular and physiological energy homeostasis. In this review, we will focus on the physiological and pathophysiological roles of the lysophospholipid mediator lysophosphatidylinositol (LPI and its receptor G-protein coupled receptor 55 (GPR55 in metabolic diseases. LPI is a bioactive lipid generated by phospholipase A (PLA family of lipases which is believed to play an important role in several diseases. Indeed LPI can affect various functions such as cell growth, differentiation and motility in a number of cell-types. Recently published data suggest that LPI plays an important role in different physiological and pathological contexts, including a role in metabolism and glucose homeostasis.

  14. Human metabolic atlas: an online resource for human metabolism.

    Science.gov (United States)

    Pornputtapong, Natapol; Nookaew, Intawat; Nielsen, Jens

    2015-01-01

    Human tissue-specific genome-scale metabolic models (GEMs) provide comprehensive understanding of human metabolism, which is of great value to the biomedical research community. To make this kind of data easily accessible to the public, we have designed and deployed the human metabolic atlas (HMA) website (http://www.metabolicatlas.org). This online resource provides comprehensive information about human metabolism, including the results of metabolic network analyses. We hope that it can also serve as an information exchange interface for human metabolism knowledge within the research community. The HMA consists of three major components: Repository, Hreed (Human REaction Entities Database) and Atlas. Repository is a collection of GEMs for specific human cell types and human-related microorganisms in SBML (System Biology Markup Language) format. The current release consists of several types of GEMs: a generic human GEM, 82 GEMs for normal cell types, 16 GEMs for different cancer cell types, 2 curated GEMs and 5 GEMs for human gut bacteria. Hreed contains detailed information about biochemical reactions. A web interface for Hreed facilitates an access to the Hreed reaction data, which can be easily retrieved by using specific keywords or names of related genes, proteins, compounds and cross-references. Atlas web interface can be used for visualization of the GEMs collection overlaid on KEGG metabolic pathway maps with a zoom/pan user interface. The HMA is a unique tool for studying human metabolism, ranging in scope from an individual cell, to a specific organ, to the overall human body. This resource is freely available under a Creative Commons Attribution-NonCommercial 4.0 International License.

  15. Human Metabolic Network: Reconstruction, Simulation, and Applications in Systems Biology

    Science.gov (United States)

    Wu, Ming; Chan, Christina

    2012-01-01

    Metabolism is crucial to cell growth and proliferation. Deficiency or alterations in metabolic functions are known to be involved in many human diseases. Therefore, understanding the human metabolic system is important for the study and treatment of complex diseases. Current reconstructions of the global human metabolic network provide a computational platform to integrate genome-scale information on metabolism. The platform enables a systematic study of the regulation and is applicable to a wide variety of cases, wherein one could rely on in silico perturbations to predict novel targets, interpret systemic effects, and identify alterations in the metabolic states to better understand the genotype-phenotype relationships. In this review, we describe the reconstruction of the human metabolic network, introduce the constraint based modeling approach to analyze metabolic networks, and discuss systems biology applications to study human physiology and pathology. We highlight the challenges and opportunities in network reconstruction and systems modeling of the human metabolic system. PMID:24957377

  16. Metabolic syndrome and periodontal disease

    Directory of Open Access Journals (Sweden)

    Bharti Vipin

    2009-01-01

    Full Text Available It is important for a dentist to be well informed and updated on the latest research on the association of oral and systemic health. Of late, the metabolic syndrome has gained importance in dental literature, and metabolic syndrome and periodontal disease have been linked. Metabolic syndrome (MeS is a group of three or more (up to five interrelated metabolic abnormalities, which increases the risk of cardiovascular morbidity and mortality. Also, both MeS and periodontal disease may be linked through a common pathophysiological pathway. Some studies have been conducted to show such an association and additional studies are required to establish this association. A dental surgeon can play a major role in evaluating patients with MeS and thus prevent the development of overt cardiovascular disease.

  17. Redesigned Human Metabolic Simulator

    Science.gov (United States)

    Duffield, Bruce; Jeng, Frank; Lange, Kevin

    2008-01-01

    A design has been formulated for a proposed improved version of an apparatus that simulates atmospheric effects of human respiration by introducing controlled amounts of carbon dioxide, water vapor, and heat into the air. Denoted a human metabolic simulator (HMS), the apparatus is used for testing life-support equipment when human test subjects are not available. The prior version of the HMS, to be replaced, was designed to simulate the respiratory effects of as many as four persons. It exploits the catalytic combustion of methyl acetate, for which the respiratory quotient (the molar ratio of carbon dioxide produced to oxygen consumed) is very close to the human respiratory quotient of about 0.86. The design of the improved HMS provides for simulation of the respiratory effects of as many as eight persons at various levels of activity. The design would also increase safety by eliminating the use of combustion. The improved HMS (see figure) would include a computer that would exert overall control. The computer would calculate the required amounts of oxygen removal, carbon dioxide addition, water addition, and heat addition by use of empirical equations for metabolic profiles of respiration and heat. A blower would circulate air between the HMS and a chamber containing a life-support system to be tested. With the help of feedback from a mass flowmeter, the blower speed would be adjusted to regulate the rate of flow according to the number of persons to be simulated and to a temperature-regulation requirement (the air temperature would indirectly depend on the rate of flow, among other parameters). Oxygen would be removed from the circulating air by means of a commercially available molecular sieve configured as an oxygen concentrator. Oxygen, argon, and trace amounts of nitrogen would pass through a bed in the molecular sieve while carbon dioxide, the majority of nitrogen, and other trace gases would be trapped by the bed and subsequently returned to the chamber. If

  18. A computer model simulating human glucose absorption and metabolism in health and metabolic disease states [version 1; referees: 2 approved, 1 approved with reservations

    Directory of Open Access Journals (Sweden)

    Richard J. Naftalin

    2016-04-01

    Full Text Available A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD, non-alcoholic steatohepatitis, (NASH and type 2 diabetes mellitus, (T2DM demonstrates how when glucagon-like peptide-1, (GLP-1 is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU. When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic

  19. Lipid metabolism in Drosophila: development and disease

    Institute of Scientific and Technical Information of China (English)

    Zhonghua Liu; Xun Huang

    2013-01-01

    Proteins,nucleic acids,and lipids are three major components of the cell.Despite a few basic metabolic pathways,we know very little about lipids,compared with the explosion of knowledge about proteins and nucleic acids.How many different forms of lipids are there? What are the in vivo functions of individual lipid? How does lipid metabolism contribute to normal development and human health? Many of these questions remain unanswered.For over a century,the fruit fly Drosophila melanogaster has been used as a model organism to study basic biological questions.In recent years,increasing evidences proved that Drosophila models are highly valuable for lipid metabolism and energy homeostasis researches.Some recent progresses of lipid metabolic regulation during Drosophila development and in Drosophila models of human diseases will be discussed in this review.

  20. Human risk of diseases associated with red meat intake: Analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid.

    Science.gov (United States)

    Alisson-Silva, Frederico; Kawanishi, Kunio; Varki, Ajit

    2016-10-01

    One of the most consistent epidemiological associations between diet and human disease risk is the impact of red meat consumption (beef, pork, and lamb, particularly in processed forms). While risk estimates vary, associations are reported with all-cause mortality, colorectal and other carcinomas, atherosclerotic cardiovascular disease, type II diabetes, and possibly other inflammatory processes. There are many proposed explanations for these associations, some long discussed in the literature. Attempts to explain the effects of red meat consumption have invoked various red meat-associated agents, including saturated fat, high salt intake, Trimethylamine-N-oxide (TMAO) generation by microbiota, and environmental pollutants contaminating red meat, none of which are specific for red meat. Even the frequently mentioned polycyclic aromatic carcinogens arising from high temperature cooking methods are not red meat specific, as these are also generated by grilling poultry or fish, as well as by other forms of cooking. The traditional explanations that appear to be more red meat specific invoke the impact of N-nitroso compounds, heme iron, and the potential of heme to catalyze endogenous nitrosation. However, heme can be denatured by cooking, high levels of plasma hemopexin will block its tissue delivery, and much higher amounts of heme likely originate from red blood cell breakdown in vivo. Therefore, red meat-derived heme could only contribute to colorectal carcinoma risk, via direct local effects. Also, none of these mechanisms explain the apparent human propensity i.e., other carnivores have not been reported at high risk for all these diseases. A more recently proposed hypothesis involves infectious agents in beef from specific dairy cattle as agents of colorectal cancer. We have also described another mechanistic explanation for the human propensity for risk of red-meat associated diseases that is consistent with most observations: metabolic incorporation of a non-human

  1. Macrophage Polarization in Metabolism and Metabolic Disease

    Directory of Open Access Journals (Sweden)

    Anna Meiliana

    2013-08-01

    Full Text Available BACKGROUND: Obesity is now recognized as the main cause of the worldwide epidemic of type 2 diabetes. Obesity-associated chronic inflammation is a contributing key factor for type 2 diabetes and cardiovascular disease. Numbers of studies have clearly demonstrated that the immune system and metabolism are highly integrated. CONTENT: Macrophages are an essential component of innate immunity and play a central role in inflammation and host defense. Moreover, these cells have homeostatic functions beyond defense, including tissue remodeling in ontogenesis and orchestration of metabolic functions. Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to interferons (IFNs, toll-like receptor (TLR, or interleukin (IL-4/IL-13 signals, macrophages undergo M1 (classical or M2 (alternative activation. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1, M2 or M2-like polarized activation. SUMMARY: In response to various signals, macrophages may undergo classical M1 activation (stimulated by TLR ligands and IFN-γ or alternative M2 activation (stimulated by IL-4/IL-13; these states mirror the T helper (Th1–Th2 polarization of T cells. Pathology is frequently associated with dynamic changes in macrophage activation, with classically activated M1 cells implicate in initiating and sustaining inflammation, meanwhile M2 or M2-like activated cells associated with resolution or smoldering chronic inflammation. Identification of the mechanisms and molecules that are associated with macrophage plasticity and polarized activation provides a basis for macrophage centered diagnostic and therapeutic strategies. KEYWORDS: obesity, adipose tissue, inflammation, macrophage polarization.

  2. [The Idiopathic Parkinson's disease: A metabolic disease?].

    Science.gov (United States)

    Rieu, I; Boirie, Y; Morio, B; Derost, P; Ulla, M; Marques, A; Debilly, B; Bannier, S; Durif, F

    2010-10-01

    Parkinson's disease is a neurodegenerative disorder clinically characterized by motor impairments (tremor, bradykinesia, rigidity and postural instability) associated or not with non-motor complications (cognitive disorders, dysautonomia). Most of patients loose weight during evolution of their disease. Dysregulations of hypothalamus, which is considered as the regulatory center of satiety and energy metabolism, could play a major role in this phenomenon. Deep brain stimulation of the subthalamic nucleus (NST) is an effective method to treat patients with advanced Parkinson's disease providing marked improvement of motor impairments. This chirurgical procedure also induces a rapid and strong body weight gain and sometimes obesity. This post-operative weight gain, which exceeds largely weight lost recorded in non-operated patient, could be responsible of metabolic disorders (such as diabetes) and cardiovascular diseases. This review describes body weight variations generated by Parkinson' disease and deep brain stimulation of the NST, and focuses on metabolic disorders capable to explain them. Finally, this review emphasizes on the importance of an adequate nutritional follow up care for parkinsonian patient.

  3. Congenital metabolic diseases: Diagnosis and treatment

    Energy Technology Data Exchange (ETDEWEB)

    Wapnir, R.A.

    1985-01-01

    This book contains eight parts, each consisting of several papers. The part titles are: The Heritage of Sir Archibald Garrod; New Approaches to the Diagnosis and Treatment of Genetic Disease; Achievements, New Trends, and Policies in the Detection of Inborn Errors of Metabolism; Disorders of Amino Acid Metabolism; Diseases of Energy Metabolism; Problems of Abnormal Storage Diseases; Inherited Diseases of Membrane Transport and Receptors; and Inborn Errors of Purine Metabolism and Urea Synthesis.

  4. Linking Microbiota to Human Diseases

    DEFF Research Database (Denmark)

    Wu, Hao; Tremaroli, Valentina; Bäckhed, F

    2015-01-01

    diabetes (T2D), and irritable bowel syndrome, and some animal experiments have suggested causality. However, few studies have validated causality in humans and the underlying mechanisms remain largely to be elucidated. We discuss how systems biology approaches combined with new experimental technologies......The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2...... may disentangle some of the mechanistic details in the complex interactions of diet, microbiota, and host metabolism and may provide testable hypotheses for advancing our current understanding of human-microbiota interaction....

  5. Intestinal Microbiota and Metabolic Diseases: Pharmacological Implications.

    Science.gov (United States)

    Shen, Liang; Ji, Hong-Fang

    2016-03-01

    An increasing number of studies show that alterations in intestinal microbiota are linked with metabolic diseases. Here, we propose that intestinal microbiota regulation by polyphenols may be an important mechanism underlying their therapeutic benefits for metabolic diseases. This helps elucidate the intriguing pharmacology of polyphenols and optimize the treatment of metabolic diseases.

  6. Metabolism of phthalates in humans

    DEFF Research Database (Denmark)

    Frederiksen, Hanne; Skakkebaek, Niels E; Andersson, Anna-Maria

    2007-01-01

    on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Therefore, exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. The metabolic pathways of phthalate metabolites excreted in human urine are partly known for some......Phthalates are synthetic compounds widely used as plasticisers, solvents and additives in many consumer products. Several animal studies have shown that some phthalates possess endocrine disrupting effects. Some of the effects of phthalates seen in rats are due to testosterone lowering effects...... phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate...

  7. Metabolism of phthalates in humans

    DEFF Research Database (Denmark)

    Frederiksen, Hanne; Skakkebaek, Niels E; Andersson, Anna-Maria

    2007-01-01

    phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate...

  8. Metabolic syndrome and gallstone disease.

    Science.gov (United States)

    Chen, Li-Ying; Qiao, Qiao-Hua; Zhang, Shan-Chun; Chen, Yu-Hao; Chao, Guan-Qun; Fang, Li-Zheng

    2012-08-21

    To investigate the association between metabolic syndrome (MetS) and the development of gallstone disease (GSD). A cross-sectional study was conducted in 7570 subjects (4978 men aged 45.0 ± 8.8 years, and 2592 women aged 45.3 ± 9.5 years) enrolled from the physical check-up center of the hospital. The subjects included 918 patients with gallstones (653 men and 265 women) and 6652 healthy controls (4325 men and 2327 women) without gallstones. Body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose (FPG) and serum lipids and lipoproteins levels were measured. Colorimetric method was used to measure cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Dextrose oxidizing enzyme method was used to measure FPG. Subjects were asked to complete a questionnaire that enquired about the information on demographic data, age, gender, histories of diabetes mellitus, hypertension, and chronic liver disease and so on. Metabolic syndrome was diagnosed according to the Adult Treatment Panel III (ATP III) criteria. Gallstones were defined by the presence of strong intraluminal echoes that were gravity-dependent or attenuated ultrasound transmission. Among the 7570 subjects, the prevalence of the gallstone disease was 12.1% (13.1% in men and 10.2% in women). BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose and serum triglyceride (TG) in cases group were higher than in controls, while serum high-density lipid was lower than in controls. There were significant differences in the waist circumference, blood pressure, FPG and TG between cases and controls. In an age-adjusted logistic regression model, metabolic syndrome was associated with gallstone disease. The age-adjusted odds ratio of MetS for GSD in men was 1.29 [95% confidence interval (CI), 1.09-1.52; P = 0.0030], and 1.68 (95% CI, 1.26-2.25; P = 0.0004) in women; the overall age-adjusted odds ratio of

  9. Metabolic hypothesis for human altriciality.

    Science.gov (United States)

    Dunsworth, Holly M; Warrener, Anna G; Deacon, Terrence; Ellison, Peter T; Pontzer, Herman

    2012-09-18

    The classic anthropological hypothesis known as the "obstetrical dilemma" is a well-known explanation for human altriciality, a condition that has significant implications for human social and behavioral evolution. The hypothesis holds that antagonistic selection for a large neonatal brain and a narrow, bipedal-adapted birth canal poses a problem for childbirth; the hominin "solution" is to truncate gestation, resulting in an altricial neonate. This explanation for human altriciality based on pelvic constraints persists despite data linking human life history to that of other species. Here, we present evidence that challenges the importance of pelvic morphology and mechanics in the evolution of human gestation and altriciality. Instead, our analyses suggest that limits to maternal metabolism are the primary constraints on human gestation length and fetal growth. Although pelvic remodeling and encephalization during hominin evolution contributed to the present parturitional difficulty, there is little evidence that pelvic constraints have altered the timing of birth.

  10. Metabolic bone disease of prematurity

    Directory of Open Access Journals (Sweden)

    Stacy E. Rustico, MD

    2014-09-01

    Full Text Available Metabolic bone disease (MBD of prematurity remains a significant problem for preterm, chronically ill neonates. The definition and recommendations for screening and treatment of MBD vary in the literature. A recent American Academy of Pediatrics Consensus Statement may help close the gap in institutional variation, but evidence based practice guidelines remain obscure due to lack of normative data and clinical trials for preterm infants. This review highlights mineral homeostasis physiology, current recommendations in screening and monitoring, prevention and treatment strategies, and an added perspective of a bone health team serving a high volume referral neonatal intensive care center.

  11. Energy metabolism during human pregnancy.

    Science.gov (United States)

    Forsum, Elisabet; Löf, Marie

    2007-01-01

    This review summarizes information regarding how human energy metabolism is affected by pregnancy, and current estimates of energy requirements during pregnancy are presented. Such estimates can be calculated using either increases in basal metabolic rate (BMR) or increases in total energy expenditure (TEE). The two modes of calculation give similar results for a complete pregnancy but different distributions of energy requirements in the three trimesters. Recent information is presented regarding the effect of pregnancy on BMR, TEE, diet-induced thermogenesis, and physical activity. The validity of energy intake (EI) data recently assessed in well-nourished pregnant women was evaluated using information regarding energy metabolism during pregnancy. The results show that underreporting of EI is common during pregnancy and indicate that additional longitudinal studies, taking the total energy budget during pregnancy into account, are needed to satisfactorily define energy requirements during the three trimesters of gestation.

  12. Metabolic syndrome and gallstone disease

    Institute of Scientific and Technical Information of China (English)

    Li-Ying Chen; Qiao-Hua Qiao; Shan-Chun Zhang; Yu-Hao Chen; Guan-Qun Chao; Li-Zheng Fang

    2012-01-01

    AIM:To investigate the association between metabolic syndrome (MetS) and the development of gallstone disease (GSD).METHODS:A cross-sectional study was conducted in 7570 subjects (4978 men aged 45.0 ± 8.8 years,and 2592 women aged 45.3 ± 9.5 years) enrolled from the physical check-up center of the hospital.The subjects included 918 patients with gallstones (653 men and 265 women) and 6652 healthy controls (4325 men and 2327 women) without gallstones.Body mass index (BMI),waist circumference,blood pressure,fasting plasma glucose (FPG) and serum lipids and lipoproteins levels were measured.Colorimetric method was used to measure cholesterol,high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).Dextrose oxidizing enzyme method was used to measure FPG.Subjects were asked to complete a questionnaire that enquired about the information on demographic data,age,gender,histories of diabetes mellitus,hypertension,and chronic liver disease and so on.Metabolic syndrome was diagnosed according to the Adult Treatment Panel Ⅲ (ATP Ⅲ) criteria.Gallstones were defined by the presence of strong intraluminal echoes that were gravity-dependent or attenuated ultrasound transmission.RESULTS:Among the 7570 subjects,the prevalence of the gallstone disease was 12.1% (13.1% in men and 10.2% in women).BMI,waist circumference,systolic blood pressure,diastolic blood pressure,fasting blood glucose and serum triglyceride (TG) in cases group were higher than in controls,while serum high-density lipid was lower than in controls.There were significant differences in the waist circumference,blood pressure,FPG and TG between cases and controls.In an ageadjusted logistic regression model,metabolic syndrome was associated with gallstone disease.The age-adjusted odds ratio of MetS for GSD in men was 1.29 [95%confidence interval (CI),1.09-1.52; P =0.0030],and 1.68 (95% CI,1.26-2.25; P =0.0004) in women; the overall age-adjusted odds ratio of MetS for

  13. Metabolism of phthalates in humans.

    Science.gov (United States)

    Frederiksen, Hanne; Skakkebaek, Niels E; Andersson, Anna-Maria

    2007-07-01

    Phthalates are synthetic compounds widely used as plasticisers, solvents and additives in many consumer products. Several animal studies have shown that some phthalates possess endocrine disrupting effects. Some of the effects of phthalates seen in rats are due to testosterone lowering effects on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Therefore, exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. The metabolic pathways of phthalate metabolites excreted in human urine are partly known for some phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP); and their monoester metabolites. Urine, however, contains relatively more of the secondary metabolites of DEHP and DiNP, as well as the monoester phthalates of the more short-branched phthalates. This differential distribution is of special concern as, in particular, the hydrophobic phthalates and their metabolites are shown to have adverse effects following in utero and lactational exposures in animal studies.

  14. Exploring metabolic dysfunction in chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Slee Adrian D

    2012-04-01

    Full Text Available Abstract Impaired kidney function and chronic kidney disease (CKD leading to kidney failure and end-stage renal disease (ESRD is a serious medical condition associated with increased morbidity, mortality, and in particular cardiovascular disease (CVD risk. CKD is associated with multiple physiological and metabolic disturbances, including hypertension, dyslipidemia and the anorexia-cachexia syndrome which are linked to poor outcomes. Specific hormonal, inflammatory, and nutritional-metabolic factors may play key roles in CKD development and pathogenesis. These include raised proinflammatory cytokines, such as interleukin-1 and −6, tumor necrosis factor, altered hepatic acute phase proteins, including reduced albumin, increased C-reactive protein, and perturbations in normal anabolic hormone responses with reduced growth hormone-insulin-like growth factor-1 axis activity. Others include hyperactivation of the renin-angiotensin aldosterone system (RAAS, with angiotensin II and aldosterone implicated in hypertension and the promotion of insulin resistance, and subsequent pharmacological blockade shown to improve blood pressure, metabolic control and offer reno-protective effects. Abnormal adipocytokine levels including leptin and adiponectin may further promote the insulin resistant, and proinflammatory state in CKD. Ghrelin may be also implicated and controversial studies suggest activities may be reduced in human CKD, and may provide a rationale for administration of acyl-ghrelin. Poor vitamin D status has also been associated with patient outcome and CVD risk and may indicate a role for supplementation. Glucocorticoid activities traditionally known for their involvement in the pathogenesis of a number of disease states are increased and may be implicated in CKD-associated hypertension, insulin resistance, diabetes risk and cachexia, both directly and indirectly through effects on other systems including activation of the mineralcorticoid

  15. The in vitro effects of Newcastle disease virus on the metabolic and antibacterial functions of human neutrophils

    Energy Technology Data Exchange (ETDEWEB)

    Faden, H.; Humbert, J.; Lee, J.; Sutyla, P.; Ogra, P.L.

    1981-08-01

    Live Newcastle disease virus (NDV) was used to investigate the in vitro effects of a viral infection on phagocytosis, chemiluminescence generation, superoxide production, oxygen consumption, NADPH-oxidase activity, and intracellular killing of bacteria by Ficoll-Hypaque separated human neutrophils. Phagocytosis of oil red O particles by NDV-treated PMN was inhibited by 50%. Chemiluminescence by PMN was inhibited 79% after zymosan stimulation and 86% after tetradeconyl phorbol acetate stimulation. Superoxide generation was inhibited by 68%. Oxygen consumption was inhibited in the presence of NDV by 37% after stimulation with phorbol myristate acetate, while membrane-associated NADPH-enzyme activity was decreased by 19%. The percent of surviving intracellular S. aureus was significantly elevated in NDV-treated PMN after 60 and 120 min of incubation. Purified bacterial neuraminidase markedly suppressed chemiluminescence, while neuraminic acid blocked the effects of the virus. These observations suggest that infections with myxoviruses may suppress a number of vital neutrophil functions. It appears that the effects may be partly mediated by the interaction of viral neuraminidase with the external neutrophil membrane.

  16. Human adipose dynamics and metabolic health.

    Science.gov (United States)

    Feng, Bin; Zhang, Tracy; Xu, Haiyan

    2013-04-01

    The two types of adipose tissue in humans, white and brown, have distinct developmental origins and functions. Human white adipose tissue plays a pivotal role in maintaining whole-body energy homeostasis by storing triglycerides when energy is in surplus, releasing free fatty acids as a fuel during energy shortage, and secreting adipokines that are important for regulating lipid and glucose metabolism. The size of white adipose mass needs to be kept at a proper set point. Dramatic expansion of white fat mass causes obesity--now become a global epidemic disease--and increases the risk for the development of many life-threatening diseases. The absence of white adipose tissue or abnormal white adipose tissue redistribution leads to lipodystrophy, a condition often associated with metabolic disorders. Brown adipose tissue is a thermogenic organ whose mass is inversely correlated with body mass index and age. Therapeutic approaches targeting adipose tissue have been proven to be effective in improving obesity-related metabolic disorders, and promising new therapies could be developed in the near future. © 2013 New York Academy of Sciences.

  17. Human neural stem cell transplantation rescues cognitive defects in APP/PS1 model of Alzheimer's disease by enhancing neuronal connectivity and metabolic activity

    Directory of Open Access Journals (Sweden)

    Xueyuan Li

    2016-11-01

    Full Text Available Alzheimer’s disease (AD, the most frequent type of dementia, is featured by Aβ pathology, neural degeneration and cognitive decline. To date, there is no cure for this disease. Neural stem cell (NSC transplantation provides new promise for treating AD. Many studies report that intra-hippocampal transplantation of murine NSCs improved cognition in rodents with AD by alleviating neurodegeneration via neuronal complement or replacement. However, few reports examined the potential of human NSC transplantation for AD. In this study, we implanted human brain-derived NSCs (hNSCs into bilateral hippocampus of an APP/PS1 transgenic mouse model of AD to test the effects of hNSC transplantation on Alzheimer’s behavior and neuropathology. Six weeks later, transplanted hNSCs engrafted into the brains of AD mice, migrated dispersedly in broad brain regions, and some of them differentiated into neural cell types of central nervous system. The hNSC transplantation restored the recognition, learning and memory deficits but not anxiety tasks in AD mice. Although Aβ plaques were not significantly reduced, the neuronal, synaptic and nerve fiber density was significantly increased in the frontal cortex and hippocampus of hNSC-treated AD mice, suggesting of improved neuronal connectivity in AD brains after hNSC transplantation. Ultrastructural analysis confirmed that synapses and nerve fibers maintained relatively well-structured shapes in these mice. Furthermore, in-vivo magnetic resonance spectroscopy showed that hNSC-treated mice had notably increased levels of NAA and Glu in the frontal cortex and hippocampus, suggesting that neuronal metabolic activity was improved in AD brains after hNSC transplantation. These results suggest that transplanted hNSCs rescued Alzheimer’s cognition by enhancing neuronal connectivity and metabolic activity through a compensation mechanism in APP/PS1 mice. This study provides preclinical evidence that hNSC transplantation

  18. The Use of Signal-Transduction and Metabolic 1 Pathways to Predict Human Disease Targets from Electric and Magnetic Fields using Literature-Based In Vitro Microarray Data from 2002 to 2011

    Directory of Open Access Journals (Sweden)

    Fred Parham

    2016-09-01

    Full Text Available Using in-vitro data in human cell lines, several research groups have investigated changes in gene expression in cellular systems following exposure to extremely low frequency (ELF and radiofrequency (RF electromagnetic fields (EMF. For ELF EMF, we obtained 5 studies with complete microarray data and 3 studies with only lists of significantly altered genes. Likewise, for RF EMF we obtained 13 complete microarray data sets and 5 limited datasets. Plausible linkages between exposure to ELF and RF EMF and human diseases were identified using a three-step process: a linking genes associated with classes of human diseases to molecular pathways; b linking pathways to ELF and RF EMF microarray data; and c identifying associations between human disease and EMF exposures where the pathways are significantly similar. A total of 60 pathways were associated with human diseases, mostly focused on basic cellular functions like JAK-STAT signaling or metabolic functions like xenobiotic metabolism by cytochrome P450 enzymes. ELF EMF datasets were sporadically linked to human diseases but no clear pattern emerged. Individual data sets showed some linkage to cancer, chemical dependency, metabolic disorders and neurological disorders. RF EMF datasets were not strongly linked to any disorders. Based on these analyses, the most promising area for further research would be to focus on EMF and neurological function and disorders.

  19. Human liver microsomal metabolism of (+)-discodermolide.

    Science.gov (United States)

    Fan, Yun; Schreiber, Emanuel M; Day, Billy W

    2009-10-01

    The polyketide natural product (+)-discodermolide is a potent microtubule stabilizer that has generated considerable interest in its synthetic, medicinal, and biological chemistry. It progressed to early clinical oncology trials, where it showed some efficacy in terms of disease stabilization but also some indications of causing pneumotoxicity. Remarkably, there are no reports of its metabolism. Here, we examined its fate in mixed human liver microsomes. Due to limited availability of the agent, we chose a nanoflow liquid chromatography-electrospray ionization-mass spectrometry analytical approach employing quadrupolar ion trap and quadrupole-quadrupole-time-of-flight instruments for these studies. (+)-Discodermolide was rapidly converted to eight metabolites, with the left-side lactone (net oxidation) and the right-side diene (epoxidation followed by hydrolysis, along with an oxygen insertion product) being the most metabolically labile sites. Other sites of metabolism were the allylic and pendant methyl moieties in the C12-C14 region of the molecule. The results provide information on the metabolic soft spots of the molecule and can be used in further medicinal chemistry efforts to optimize discodermolide analogues.

  20. Adipocytokines in Cardiovascular and Metabolic Diseases.

    Science.gov (United States)

    Ouchi, Noriyuki

    2016-06-01

    Obesity, particularly excess visceral fat accumulation, is highly associated with the development of metabolic syndrome and atherosclerotic cardiovascular disease. Adipose tissue produces a variety of secreted proteins, referred to as adipocytokines, which directly affect nearby or remote organs. Dysregulation of adipocytokines caused by obese conditions contributes to the pathogenesis of various metabolic and cardiovascular disorders. This review focuses on the significance of several adipocytokines that potentially exert beneficial actions on obesity-related diseases, including atherosclerosis and ischemic heart disease.

  1. New paradigms for metabolic modeling of human cells

    DEFF Research Database (Denmark)

    Mardinoglu, Adil; Nielsen, Jens

    2015-01-01

    Abnormalities in cellular functions are associated with the progression of human diseases, often resulting in metabolic reprogramming. GEnome-scale metabolic Models (GEMs) have enabled studying global metabolic reprogramming in connection with disease development in a systematic manner. Here we......, challenges in integration of cell/tissue models for simulation of whole body functions as well as integration of GEMs with other biological networks for generating complete cell/tissue models are presented....... review recent work on reconstruction of GEMs for human cell/tissue types and cancer, and the use of GEMs for identification of metabolic changes occurring in response to disease development. We further discuss how GEMs can be used for the development of efficient therapeutic strategies. Finally...

  2. Human adipose tissue stem cells: relevance in the pathophysiology of obesity and metabolic diseases and therapeutic applications.

    Science.gov (United States)

    Cignarelli, Angelo; Perrini, Sebastio; Ficarella, Romina; Peschechera, Alessandro; Nigro, Pasquale; Giorgino, Francesco

    2012-12-10

    Stem cells are unique cells exhibiting self-renewing properties and the potential to differentiate into multiple specialised cell types. Totipotent or pluripotent stem cells are generally abundant in embryonic or fetal tissues, but the use of discarded embryos as sources of these cells raises challenging ethical problems. Adult stem cells can also differentiate into a wide variety of cell types. In particular, adult adipose tissue contains a pool of abundant and accessible multipotent stem cells, designated as adipose-derived stem cells (ASCs), that are able to replicate as undifferentiated cells, to develop as mature adipocytes and to differentiate into multiple other cell types along the mesenchymal lineage, including chondrocytes, myocytes and osteocytes, and also into cells of endodermal and neuroectodermal origin, including beta-cells and neurons, respectively. An impairment in the differentiation potential and biological functions of ASCs may contribute to the development of obesity and related comorbidities. In this review, we summarise different aspects of the ASCs with special reference to the isolation and characterisation of these cell populations, their relation to the biochemical features of the adipose tissue depot of origin and to the metabolic characteristics of the donor subject and discuss some prospective therapeutic applications.

  3. Human Environmental Disease Network

    DEFF Research Database (Denmark)

    Taboureau, Olivier; Audouze, Karine

    2017-01-01

    During the past decades, many epidemiological, toxicological and biological studies have been performed to assess the role of environmental chemicals as potential toxicants for diverse human disorders. However, the relationships between diseases based on chemical exposure have been rarely studied...... by computational biology. We developed a human environmental disease network (EDN) to explore and suggest novel disease-disease and chemical-disease relationships. The presented scored EDN model is built upon the integration on systems biology and chemical toxicology using chemical contaminants information...

  4. Metabolic resting-state brain networks in health and disease.

    Science.gov (United States)

    Spetsieris, Phoebe G; Ko, Ji Hyun; Tang, Chris C; Nazem, Amir; Sako, Wataru; Peng, Shichun; Ma, Yilong; Dhawan, Vijay; Eidelberg, David

    2015-02-24

    The delineation of resting state networks (RSNs) in the human brain relies on the analysis of temporal fluctuations in functional MRI signal, representing a small fraction of total neuronal activity. Here, we used metabolic PET, which maps nonfluctuating signals related to total activity, to identify and validate reproducible RSN topographies in healthy and disease populations. In healthy subjects, the dominant (first component) metabolic RSN was topographically similar to the default mode network (DMN). In contrast, in Parkinson's disease (PD), this RSN was subordinated to an independent disease-related pattern. Network functionality was assessed by quantifying metabolic RSN expression in cerebral blood flow PET scans acquired at rest and during task performance. Consistent task-related deactivation of the "DMN-like" dominant metabolic RSN was observed in healthy subjects and early PD patients; in contrast, the subordinate RSNs were activated during task performance. Network deactivation was reduced in advanced PD; this abnormality was partially corrected by dopaminergic therapy. Time-course comparisons of DMN loss in longitudinal resting metabolic scans from PD and Alzheimer's disease subjects illustrated that significant reductions appeared later for PD, in parallel with the development of cognitive dysfunction. In contrast, in Alzheimer's disease significant reductions in network expression were already present at diagnosis, progressing over time. Metabolic imaging can directly provide useful information regarding the resting organization of the brain in health and disease.

  5. Abnormal erythrocyte metabolism in hepatic disease.

    Science.gov (United States)

    Smith, J R; Kay, N E; Gottlieb, A J; Oski, F A

    1975-12-01

    Erythrocyte (RBC) metabolic studies were done on 114 patients with severe hepatic disease. Heinz body formation after incubation of RBCs with acetyl phenylhydrazine was found to be significantly higher in patients than in controls. RBC-reduced glutathione levels were lower than those of controls both before and after incubation with acetyl phenylhydrazine, and patients with the highest Heinz body counts had the lowest reduced glutathione levels. RBC methylene blue-stimulated hexose monophosphate (HMP) shunt metabolism and glucose recycling through the shunt were significantly lower in patients with active hepatic disease than in controls. There was no difference in resting HMP shunt activity or in resting recycling of glucose. Despite impairment of shunt metabolism, total glucose consumption was greater in patients than in controls. The patients with the lowest stimulated HMP shunt metabolism and glucose recycling had the highest Heinz body counts, lowest reduced glutathione, and highest total glucose consumption. A continuum of abnormal shunt metabolism was seen, from a mild reduction of stimulated HMP shunt activity to a severe combined decrease in both the HMP shunt and glucose recycling. When measured, glutathione reductase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, and transketolase were normal or increased. Sequential studies were done on 11 patients who had abnormal metabolic studies. Coincident with improvement of HMP shunt metabolism, the Heinz body counts became lower, reduced glutathione higher, hematocrit higher, and liver function improved. Impaired HMP shunt metabolism appears to be a common, acquired RBC abnormality in patients with severe, active liver disease.

  6. Bile acid signaling in metabolic disease and drug therapy.

    Science.gov (United States)

    Li, Tiangang; Chiang, John Y L

    2014-10-01

    Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid-activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein-coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver.

  7. Circadian Rhythms, Metabolism, and Chrononutrition in Rodents and Humans123

    Science.gov (United States)

    Johnston, Jonathan D; Scheer, Frank A; Turek, Fred W

    2016-01-01

    Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial responses. Recent work has elucidated the metabolic roles of circadian clocks in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle. For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis. This review explains mechanistic insights gained from transgenic animal studies and how these data are being translated into the study of human genetics and physiology. The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population. PMID:26980824

  8. Characterizing metabolic changes in human colorectal cancer.

    Science.gov (United States)

    Williams, Michael D; Zhang, Xing; Park, Jeong-Jin; Siems, William F; Gang, David R; Resar, Linda M S; Reeves, Raymond; Hill, Herbert H

    2015-06-01

    Colorectal cancer (CRC) remains a leading cause of cancer death worldwide, despite the fact that it is a curable disease when diagnosed early. The development of new screening methods to aid in early diagnosis or identify precursor lesions at risk for progressing to CRC will be vital to improving the survival rate of individuals predisposed to CRC. Metabolomics is an advancing area that has recently seen numerous applications to the field of cancer research. Altered metabolism has been studied for many years as a means to understand and characterize cancer. However, further work is required to establish standard procedures and improve our ability to identify distinct metabolomic profiles that can be used to diagnose CRC or predict disease progression. The present study demonstrates the use of direct infusion traveling wave ion mobility mass spectrometry to distinguish metabolic profiles from CRC samples and matched non-neoplastic epithelium as well as metastatic and primary tumors at different stages of disease (T1-T4). By directly infusing our samples, the analysis time was reduced significantly, thus increasing the speed and efficiency of this method compared to traditional metabolomics platforms. Partial least squares discriminant analysis was used to visualize differences between the metabolic profiles of sample types and to identify the specific m/z features that led to this differentiation. Identification of the distinct m/z features was made using the human metabolome database. We discovered alterations in fatty acid biosynthesis and oxidative, glycolytic, and polyamine pathways that distinguish tumors from non-malignant colonic epithelium as well as various stages of CRC. Although further studies are needed, our results indicate that colonic epithelial cells undergo metabolic reprogramming during their evolution to CRC, and the distinct metabolites could serve as diagnostic tools or potential targets in therapy or primary prevention. Graphical Abstract

  9. Can We Prevent Obesity-Related Metabolic Diseases by Dietary Modulation of the Gut Microbiota?

    Science.gov (United States)

    Brahe, Lena K; Astrup, Arne; Larsen, Lesli H

    2016-01-01

    Obesity increases the risk of type 2 diabetes, cardiovascular diseases, and certain cancers, which are among the leading causes of death worldwide. Obesity and obesity-related metabolic diseases are characterized by specific alterations in the human gut microbiota. Experimental studies with gut microbiota transplantations in mice and in humans indicate that a specific gut microbiota composition can be the cause and not just the consequence of the obese state and metabolic disease, which suggests a potential for gut microbiota modulation in prevention and treatment of obesity-related metabolic diseases. In addition, dietary intervention studies have suggested that modulation of the gut microbiota can improve metabolic risk markers in humans, but a causal role of the gut microbiota in such studies has not yet been established. Here, we review and discuss the role of the gut microbiota in obesity-related metabolic diseases and the potential of dietary modulation of the gut microbiota in metabolic disease prevention and treatment.

  10. Can We Prevent Obesity-Related Metabolic Diseases by Dietary Modulation of the Gut Microbiota?1

    Science.gov (United States)

    2016-01-01

    Obesity increases the risk of type 2 diabetes, cardiovascular diseases, and certain cancers, which are among the leading causes of death worldwide. Obesity and obesity-related metabolic diseases are characterized by specific alterations in the human gut microbiota. Experimental studies with gut microbiota transplantations in mice and in humans indicate that a specific gut microbiota composition can be the cause and not just the consequence of the obese state and metabolic disease, which suggests a potential for gut microbiota modulation in prevention and treatment of obesity-related metabolic diseases. In addition, dietary intervention studies have suggested that modulation of the gut microbiota can improve metabolic risk markers in humans, but a causal role of the gut microbiota in such studies has not yet been established. Here, we review and discuss the role of the gut microbiota in obesity-related metabolic diseases and the potential of dietary modulation of the gut microbiota in metabolic disease prevention and treatment. PMID:26773017

  11. Nutrient sensing and inflammation in metabolic diseases.

    Science.gov (United States)

    Hotamisligil, Gökhan S; Erbay, Ebru

    2008-12-01

    The proper functioning of the pathways that are involved in the sensing and management of nutrients is central to metabolic homeostasis and is therefore among the most fundamental requirements for survival. Metabolic systems are integrated with pathogen-sensing and immune responses, and these pathways are evolutionarily conserved. This close functional and molecular integration of the immune and metabolic systems is emerging as a crucial homeostatic mechanism, the dysfunction of which underlies many chronic metabolic diseases, including type 2 diabetes and atherosclerosis. In this Review we provide an overview of several important networks that sense and manage nutrients and discuss how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.

  12. Metabolically healthy obesity and ischemic heart disease

    DEFF Research Database (Denmark)

    Hansen, Louise; Netterstrøm, Marie K.; Johansen, Nanna B.

    2017-01-01

    Context: Recent studies have suggested that a subgroup of obese individuals is not at increased risk of obesity-related complications. This subgroup has been referred to as metabolically healthy obese. Objective: To investigate whether obesity is a risk factor for development of ischemic heart...... disease (IHD) irrespective of metabolic health. Design: In all, 6238 men and women from the Danish prospective Inter99 study were followed during 10.6 (standard deviation = 1.7) years. Setting: General community. Participants: Participants were classified according to body mass index and four metabolic...

  13. Hepatic diseases related to triglyceride metabolism.

    Science.gov (United States)

    Aguilera-Méndez, Asdrubal; Álvarez-Delgado, Carolina; Hernández-Godinez, Daniel; Fernandez-Mejia, Cristina

    2013-10-01

    Triglycerides participate in key metabolic functions such as energy storage, thermal insulation and as deposit for essential and non-essential fatty acids that can be used as precursors for the synthesis of structural and functional phospholipids. The liver is a central organ in the regulation of triglyceride metabolism, and it participates in triglyceride synthesis, export, uptake and oxidation. The metabolic syndrome and associated diseases are among the main concerns of public health worldwide. One of the metabolic syndrome components is impaired triglyceride metabolism. Diseases associated with the metabolic syndrome promote the appearance of hepatic alterations e.g., non-alcoholic steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. In this article, we review the molecular actions involved in impaired triglyceride metabolism and its association with hepatic diseases. We discuss mechanisms that reconcile the chronic inflammation and insulin resistance, and new concepts on the role of intestinal micro-flora permeability and proliferation in fatty liver etiology. We also describe the participation of oxidative stress in the progression of events leading from steatosis to steatohepatitis and fibrosis. Finally, we provide information regarding the mechanisms that link fatty acid accumulation during steatosis with changes in growth factors and cytokines that lead to the development of neoplastic cells. One of the main medical concerns vis-a-vis hepatic diseases is the lack of symptoms at the onset of the illness and, as result, its late diagnosis. The understandings of the molecular mechanisms that underlie hepatic diseases could help design strategies towards establishing markers for their accurate and timely diagnosis.

  14. Imbalanced cholesterol metabolism in Alzheimer's disease.

    Science.gov (United States)

    Xue-shan, Zhao; Juan, Peng; Qi, Wu; Zhong, Ren; Li-hong, Pan; Zhi-han, Tang; Zhi-sheng, Jiang; Gui-xue, Wang; Lu-shan, Liu

    2016-05-01

    Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease that is mainly caused by β-amyloid accumulation. A large number of studies have shown that elevated cholesterol levels may perform a function in AD pathology, and several cholesterol-related gene polymorphisms are associated with this disease. Although numerous studies have shown the important function of cholesterol in AD pathogenesis and development, the underlying mechanism remains unclear. To further elucidate cholesterol metabolism disorder and AD, we first, review metabolism and regulation of the cholesterol in the brain. Second, we summarize the literature stating that hypercholesterolemia is one of the risk factors of AD. Third, we discuss the main mechanisms of abnormal cholesterol metabolism that increase the risk of AD. Finally, the relationships between AD and apolipoprotein E, PCSK9, and LRP1 are discussed in this article.

  15. Chronic kidney disease and bone metabolism.

    Science.gov (United States)

    Kazama, Junichiro James; Matsuo, Koji; Iwasaki, Yoshiko; Fukagawa, Masafumi

    2015-05-01

    Chronic kidney disease-related mineral and bone disease (CKD-MBD) is a syndrome defined as a systemic mineral metabolic disorder associated with CKD, and the term renal osteodystrophy indicates a pathomorphological concept of bone lesions associated with CKD-MBD. Cortical bone thinning, abnormalities in bone turnover and primary/secondary mineralization, elevated levels of circulating sclerostin, increased apoptosis in osteoblasts and osteocytes, disturbance of the coupling phenomenon, iatrogenic factors, accumulated micro-crackles, crystal/collagen disorientation, and chemical modification of collagen crosslinks are all possible candidates found in CKD that could promote osteopenia and/or bone fragility. Some of above factors are the consequences of abnormal systemic mineral metabolism but for others it seem unlikely. We have used the term uremic osteoporosis to describe the uremia-induced bone fragility which is not derived from abnormal systemic mineral metabolism. Interestingly, the disease aspect of uremic osteoporosis appears to be similar to that of senile osteoporosis.

  16. Peripheral cholesterol, metabolic disorders and Alzheimer's disease.

    Science.gov (United States)

    Ledesma, Maria Dolores; Dotti, Carlos Gerardo

    2012-01-01

    Strong correlations have been made between high levels of blood cholesterol and the risk to suffer Alzheimer's disease (AD). The question arises on how a peripheral event contributes to a disease that so severely affects the integrity and function of the Central Nervous System. Hypercholesterolemia has been also associated to peripheral metabolic disorders like diabetes, obesity or atherosclerosis that, in turn, predispose to AD. Here we review data, which point to alterations in blood cholesterol levels as a link between these metabolic disorders and AD. We describe and discuss common, cholesterol-related, molecular mechanisms and strategies to fight these conditions that, altogether, constitute a major cause of death in our societies.

  17. Gender and metabolic differences of gallstone diseases

    Institute of Scientific and Technical Information of China (English)

    Hui Sun; Hong Tang; Shan Jiang; Li Zeng; En-Qiang Chen; Tao-You Zhou; You-Juan Wang

    2009-01-01

    AIM: To investigate the risk factors for gallstone disease in the general population of Chengdu, China. METHODS: This study was conducted at the West China Hospital. Subjects who received a physical examination at this hospital between January and December 2007 were included. Body mass index, blood pressure, fasting plasma glucose, serum lipid and lipoproteins concentrations were analyzed. Gallstone disease was diagnosed by ultrasound or on the basis of a history of cholecystectomy because of gallstone disease. Unconditional logistic regression analysis was used to investigate the risk factors for gallstone disease, and the Chi-square test was used to analyze differences in the incidence of metabolic disorders between subjects with and without gallstone disease. RESULTS: A total of 3573 people were included, 10.7% (384/3573) of whom had gallstone diseases. Multiple logistic regression analysis indicated that the incidence of gallstone disease in subjects aged 40-64 or ≥ 65 years was significantly different from that in those aged 18-39 years ( P < 0.05); the incidence was higher in women than in men ( P < 0.05). In men, in women than in men ( P < 0.05). In men, a high level of fasting plasma glucose was obvious in gallstone disease ( P < 0.05), and in women, hypertriglyceridemia or obesity were significant in gallstone disease ( P < 0.05). CONCLUSION: We assume that age and sex are profoundly associated with the incidence of gallstone disease; the metabolic risk factors for gallstone disease were different between men and women.

  18. Metabolic interactions of agrochemicals in humans.

    Science.gov (United States)

    Hodgson, Ernest; Rose, Randy L

    2008-06-01

    Agrochemicals and other xenobiotics are metabolized by xenobiotic-metabolizing enzymes (XMEs) to products that may be more or less toxic than the parent chemical. In this regard, phase-I XMEs such as cytochrome P450s (CYPs) are of primary importance. Interactions at the level of metabolism may take place via either inhibition or induction of XMEs. Such interactions have often been investigated, in vitro, in experimental animals, using subcellular fractions such as liver microsomes, but seldom in humans or at the level of individual XME isoforms. The authors have been investigating the metabolism of a number of agrochemicals by human liver microsomes and recombinant CYP isoforms and have recently embarked on studies of the induction of XMEs in human hepatocytes. The insecticides chlorpyrifos, carbaryl, carbofuran and fipronil, as well as the repellant DEET, are all extensively metabolized by human liver microsomes and, although a number of CYP isoforms may be involved, CYP2B6 and CYP3A4 are usually the most important. Permethrin is hydrolyzed by esterase(s) present in both human liver microsomes and cytosol. A number of metabolic interactions have been observed. Chlorpyrifos and other phosphorothioates are potent inhibitors of the CYP-dependent metabolism of both endogenous substrates, such as testosterone and estradiol, and exogenous substrates, such as carbaryl, presumably as a result of the interaction of highly reactive sulfur, released during the oxidative desulfuration reaction, with the heme iron of CYP. The hydrolysis of permethrin in human liver can be inhibited by chlorpyrifos oxon and by carbaryl. Fipronil can inhibit testosterone metabolism by CYP3A4 and is an effective inducer of CYP isoforms in human hepatocytes.

  19. Diet-microbiota interactions as moderators of human metabolism.

    Science.gov (United States)

    Sonnenburg, Justin L; Bäckhed, Fredrik

    2016-07-06

    It is widely accepted that obesity and associated metabolic diseases, including type 2 diabetes, are intimately linked to diet. However, the gut microbiota has also become a focus for research at the intersection of diet and metabolic health. Mechanisms that link the gut microbiota with obesity are coming to light through a powerful combination of translation-focused animal models and studies in humans. A body of knowledge is accumulating that points to the gut microbiota as a mediator of dietary impact on the host metabolic status. Efforts are focusing on the establishment of causal relationships in people and the prospect of therapeutic interventions such as personalized nutrition.

  20. Neurodegenerative disorders and metabolic disease.

    Science.gov (United States)

    Pierre, Germaine

    2013-08-01

    Most genetic causes of neurodegenerative disorders in childhood are due to neurometabolic disease. There are over 200 disorders, including aminoacidopathies, creatine disorders, mitochondrial cytopathies, peroxisomal disorders and lysosomal storage disorders. However, diagnosis can pose a challenge to the clinician when patients present with non-specific problems like epilepsy, developmental delay, autism, dystonia and ataxia. The variety of specialist tests involved can also be daunting. This review aims to give a practical approach to the investigation and diagnosis of neurometabolic disease from the neonatal period to late childhood while prioritising disorders where there are therapeutic options. In particular, patients who have a complex clinical picture of several neurological and non-neurological features should be investigated.

  1. Vaccines for metabolic diseases: current perspectives

    Directory of Open Access Journals (Sweden)

    Morais T

    2014-09-01

    Full Text Available Tiago Morais, Sara Andrade, Sofia S Pereira, Mariana P MonteiroDepartment of Anatomy, Unit for Multidisciplinary Biomedical Research, Institute for Biomedical Sciences Abel Salazar, University of Porto, Porto, PortugalAbstract: Several metabolic disorders, such as diabetes, hypertension, dyslipidemia, and obesity, represent significant risk factors for cardiovascular disease, which is the leading cause of morbidity and mortality among adult populations in western societies. Understandably, these chronic disorders have now replaced infectious diseases as the most important public health problem and economic burden to society in most countries. Treatment of metabolic risk factors in order to prevent cardiovascular disease requires an enduring approach with multiple drugs, which can be associated with considerable costs, side effects, and a low rate of therapeutic compliance due to lack of symptoms until later stages of the disease. Since vaccines have proven to be a powerful and effective approach to preventing infectious diseases, attempts to expand the therapeutic use of vaccines into the context of highly prevalent diseases has been attracting increased research interest. Vaccination strategies for chronic diseases in particular are an exciting area of research, with new treatment targets and strategies on the horizon. This review discusses the development of innovative therapeutic agents, focusing on the use of molecular vaccines for the treatment of common and highly prevalent chronic metabolic disorders, ie, diabetes, hypertension, dyslipidemia, and obesity.Keywords: vaccines, diabetes, hypertension, dyslipidemia, obesity

  2. Human metabolic interactions of environmental chemicals.

    Science.gov (United States)

    Hodgson, Ernest; Rose, Randy L

    2007-01-01

    Investigations utilizing recombinant human xenobiotic-metabolizing enzymes as well as human hepatocytes have revealed a number of interactions not only between different environmental chemicals (ECs) but also between ECs and endogenous metabolites. Organophosphorus insecticides (OPs) are potent inhibitors of the human metabolism of carbaryl, carbofuran, DEET and fipronil, as well as the jet fuel components, nonane and naphthalene. OPs are potent irreversible inhibitors of testosterone metabolism by cytochrome P450 (CYP) 3A4 and of estradiol metabolism by CYP3A4 and CYP1A2. All of these CYP inhibitions are believed to be due to the release of reactive sulfur during CYP-catalyzed oxidative desulfuration. It has also been shown that the esterase(s) responsible for the initial step in permethrin metabolism in human liver is inhibited by both chlorpyrifos oxon and carbaryl. A number of pesticides, including chlorpyrifos, fipronil and permethrin, and the repellent, DEET, have been shown to be inducers of CYP isoforms in human hepatocytes, with fipronil being the most potent. Several agrochemicals, including fipronil and the pyrethroids, permethrin and deltamethrin, show toxicity toward human hepatocytes with fipronil being the most potent in this regard. Endosulfan-alpha, which has shown promise as a model substrate for phenotyping CYP3A4 and CYP2B6 in human liver microsomes, is also an inducer of CYP2B6, acting through the PXR receptor.

  3. 线粒体铁代谢与人类疾病的研究进展%Recent progress on mitochondrial iron metabolism and human diseases

    Institute of Scientific and Technical Information of China (English)

    杨硕菲; 夏海燕; 周迪; 李宽钰

    2012-01-01

    Two aspects of mitochondrial iron metabolism are included: iron trafficking and communication between cytosol and mitochondria; iron-sulfur clusters (Fe-S) and heme biogenesis in mitochondria and transport from mitochondria into extramitochondria. Recent investigations have identified a host of mitochondrial proteins that may play roles in the homeostasis of mitochondrial iron. For instance, mitoferrins 1 and 2 (MFRN1 and MFRN2) and ABCB10 are thought to be involved in iron trafficking from cytosol to mitochondria, while ABCB 6 and/or 7 are in reverse direction of iron trafficking. The detailed trafficking and regulation remain unknown, whereas it is suspected that a Fe-S protein as an iron sensor is involved in communication between mitochondria and extramitochondria. Mammalian Fe-S biogenesis is thought to occur mainly in mitochondria, as well as in cytosol. Totally more than 20proteins are currently found to be involved in Fe-S cluster biogenesis in eukaryotes, four of which, ISCS, ISDU, ISCU, and FXN, are considered to be core components of the machinery. Initiation and termination'of heme biogenesis take place in mitochondria. And the last step is iron insertion into protoporphrin IX by ferrochelatase to form heme. Mammalian ferrochelatase activity is 2Fe-2S-dependent. Thus, Fe-S biogenesis and regulatian play a vital role in mitochondrial iron metabolism and in whole-cell iron processing. This paper will summarize the recent progress on mitochondrial iron metabolism, particularly Fe-S cluster biogenesis and human diseases caused by impairment of Fe-S cluster assembly or trafficking.%线粒体铁代谢的研究主要包括两个方面:铁在胞质和线粒体之间的转运和调控;铁硫簇和血红素在线粒体内的合成与转运.目前认为线粒体铁的转入主要是与mitoferrin 1/2(MFRN1和MFRN2)和ABCB10有关,运出可能与ABCB6和/或ABCB7有关,转运和调控的具体机制不是很清楚,推测与某种含有铁硫簇的信号分子有

  4. A Metabolic Study of Huntington's Disease.

    Directory of Open Access Journals (Sweden)

    Rajasree Nambron

    Full Text Available Huntington's disease patients have a number of peripheral manifestations suggestive of metabolic and endocrine abnormalities. We, therefore, investigated a number of metabolic factors in a 24-hour study of Huntington's disease gene carriers (premanifest and moderate stage II/III and controls.Control (n = 15, premanifest (n = 14 and stage II/III (n = 13 participants were studied with blood sampling over a 24-hour period. A battery of clinical tests including neurological rating and function scales were performed. Visceral and subcutaneous adipose distribution was measured using magnetic resonance imaging. We quantified fasting baseline concentrations of glucose, insulin, cholesterol, triglycerides, lipoprotein (a, fatty acids, amino acids, lactate and osteokines. Leptin and ghrelin were quantified in fasting samples and after a standardised meal. We assessed glucose, insulin, growth hormone and cortisol concentrations during a prolonged oral glucose tolerance test.We found no highly significant differences in carbohydrate, protein or lipid metabolism markers between healthy controls, premanifest and stage II/III Huntington's disease subjects. For some markers (osteoprotegerin, tyrosine, lysine, phenylalanine and arginine there is a suggestion (p values between 0.02 and 0.05 that levels are higher in patients with premanifest HD, but not moderate HD. However, given the large number of statistical tests performed interpretation of these findings must be cautious.Contrary to previous studies that showed altered levels of metabolic markers in patients with Huntington's disease, our study did not demonstrate convincing evidence of abnormalities in any of the markers examined. Our analyses were restricted to Huntington's disease patients not taking neuroleptics, anti-depressants or other medication affecting metabolic pathways. Even with the modest sample sizes studied, the lack of highly significant results, despite many being tested, suggests that

  5. Inflammatory mechanisms linking obesity and metabolic disease.

    Science.gov (United States)

    Saltiel, Alan R; Olefsky, Jerrold M

    2017-01-03

    There are currently over 1.9 billion people who are obese or overweight, leading to a rise in related health complications, including insulin resistance, type 2 diabetes, cardiovascular disease, liver disease, cancer, and neurodegeneration. The finding that obesity and metabolic disorder are accompanied by chronic low-grade inflammation has fundamentally changed our view of the underlying causes and progression of obesity and metabolic syndrome. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a proinflammatory phenotype, and we are beginning to delineate the reciprocal influence of obesity and inflammation. Reviews in this series examine the activation of the innate and adaptive immune system in obesity; inflammation within diabetic islets, brain, liver, gut, and muscle; the role of inflammation in fibrosis and angiogenesis; the factors that contribute to the initiation of inflammation; and therapeutic approaches to modulate inflammation in the context of obesity and metabolic syndrome.

  6. Adipokines, Metabolic Syndrome and Rheumatic Diseases

    OpenAIRE

    Vanessa Abella; Morena Scotece; Javier Conde; Verónica López; Verónica Lazzaro; Jesús Pino; Gómez-Reino, Juan J; Oreste Gualillo

    2014-01-01

    The metabolic syndrome (MetS) is a cluster of cardiometabolic disorders that result from the increasing prevalence of obesity. The major components of MetS include insulin resistance, central obesity, dyslipidemia, and hypertension. MetS identifies the central obesity with increased risk for cardiovascular diseases (CVDs) and type-2 diabetes mellitus (T2DM). Patients with rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis...

  7. Retroviruses and human disease.

    OpenAIRE

    1987-01-01

    Over the past 25 years animal retroviruses have been favoured subjects of research by virologists, oncologists, and molecular biologists. Retroviruses have given us reverse transcriptase, oncogenes, and cloning vectors that may one day be exploited for human gene therapy. They have also given us leukaemia and the acquired immune deficiency syndrome (AIDS). Kawasaki disease and tropical spastic paraparesis are thought to be associated with retrovirus infection, and other diseases such as de Qu...

  8. Editorial; Lipids in Metabolic Health and Disease

    NARCIS (Netherlands)

    Glatz, Jan; De Groot, Renate; Hesselink, Matthijs; Schrauwen, Patrick

    2012-01-01

    Glatz, J. F. C., De Groot, R. H. M., Hesselink, K. C., & Schrauwen, P. (2011). Editorial; Lipids in Metabolic Health and Disease. Prostaglandines, Leukotrienes and Essential fatty Acids, 85, 195. DOI: 10.1016/j.plefa.2011.04.006

  9. The metabolic syndrome: a brain disease?

    NARCIS (Netherlands)

    Buijs, R.M.; Kreier, F.

    2006-01-01

    The incidence of obesity with, as consequence, a rise in associated diseases such as diabetes, hypertension and dyslipidemia--the metabolic syndrome--is reaching epidemic proportions in industrialized countries. Here, we provide a hypothesis that the biological clock which normally prepares us each

  10. Migraine, cerebrovascular disease and the metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Alexandra J Sinclair

    2012-01-01

    Full Text Available Evidence is emerging that migraine is not solely a headache disorder. Observations that ischemic stroke could occur in the setting of a migraine attack, and that migraine headaches could be precipitated by cerebral ischemia, initially highlighted a possibly association between migraine and cerebrovascular disease. More recently, large population-based studies that have demonstrated that migraineurs are at increased risk of stroke outside the setting of a migraine attack have prompted the concept that migraine and cerebrovascular disease are comorbid conditions. Explanations for this association are numerous and widely debated, particularly as the comorbid association does not appear to be confined to the cerebral circulation as cardiovascular and peripheral vascular disease also appear to be comorbid with migraine. A growing body of evidence has also suggested that migraineurs are more likely to be obese, hypertensive, hyperlipidemic and have impaired insulin sensitivity, all features of the metabolic syndrome. The comorbid association between migraine and cerebrovascular disease may consequently be explained by migraineurs having the metabolic syndrome and consequently being at increased risk of cerebrovascular disease. This review will summarise the salient evidence suggesting a comorbid association between migraine, cerebrovascular disease and the metabolic syndrome.

  11. Altered cholesterol and fatty acid metabolism in Huntington disease.

    Science.gov (United States)

    Block, Robert C; Dorsey, E Ray; Beck, Christopher A; Brenna, J Thomas; Shoulson, Ira

    2010-01-01

    Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.

  12. Metabolic heterogeneity in human lung tumors

    Science.gov (United States)

    Hensley, Christopher T.; Faubert, Brandon; Yuan, Qing; Lev-Cohain, Naama; Jin, Eunsook; Kim, Jiyeon; Jiang, Lei; Ko, Bookyung; Skelton, Rachael; Loudat, Laurin; Wodzak, Michelle; Klimko, Claire; McMillan, Elizabeth; Butt, Yasmeen; Ni, Min; Oliver, Dwight; Torrealba, Jose; Malloy, Craig R.; Kernstine, Kemp; Lenkinski, Robert E.; DeBerardinis, Ralph J.

    2015-01-01

    SUMMARY Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC metabolism in vivo using intra-operative 13C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, our data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. Our findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature. PMID:26853473

  13. Bisphenol A sulfonation is impaired in metabolic and liver disease

    Science.gov (United States)

    Yalcin, Emine B.; Kulkarni, Supriya R.; Slitt, Angela L.; King, Roberta

    2016-01-01

    Background Bisphenol A (BPA) is a widely used industrial chemical and suspected endocrine disruptor to which humans are ubiquitously exposed. Liver metabolizes and facilitates BPA excretion through glucuronidation and sulfonation. The sulfotransferase enzymes contributing to BPA sulfonation (detected in human and rodents) is poorly understood. Objectives To determine the impact of metabolic and liver disease on BPA sulfonation in human and mouse livers. Methods The capacity for BPA sulfonation was determined in human liver samples that were categorized into different stages of metabolic and liver disease (including obesity, diabetes, steatosis, and cirrhosis) and in livers from ob/ob mice. Results In human liver tissues, BPA sulfonation was substantially lower in livers from subjects with steatosis (23%), diabetes cirrhosis (16%), and cirrhosis (18%), relative to healthy individuals with non-fatty livers (100%). In livers of obese mice (ob/ob), BPA sulfonation was lower (23%) than in livers from lean wild-type controls (100%). In addition to BPA sulfonation activity, Sult1a1 protein expression decreased by 97% in obese mouse livers. Conclusion Taken together these findings establish a profoundly reduced capacity of BPA elimination via sulfonation in obese or diabetic individuals and in those with fatty or cirrhotic livers versus individuals with healthy livers. PMID:26712468

  14. The human metabolic reconstruction Recon 1 directs hypotheses of novel human metabolic functions

    Directory of Open Access Journals (Sweden)

    Thiele Ines

    2011-10-01

    Full Text Available Abstract Background Metabolic network reconstructions formalize our knowledge of metabolism. Gaps in these networks pinpoint regions of metabolism where biological components and functions are "missing." At the same time, a major challenge in the post genomic era involves characterisation of missing biological components to complete genome annotation. Results We used the human metabolic network reconstruction RECON 1 and established constraint-based modelling tools to uncover novel functions associated with human metabolism. Flux variability analysis identified 175 gaps in RECON 1 in the form of blocked reactions. These gaps were unevenly distributed within metabolic pathways but primarily found in the cytosol and often caused by compounds whose metabolic fate, rather than production, is unknown. Using a published algorithm, we computed gap-filling solutions comprised of non-organism specific metabolic reactions capable of bridging the identified gaps. These candidate solutions were found to be dependent upon the reaction environment of the blocked reaction. Importantly, we showed that automatically generated solutions could produce biologically realistic hypotheses of novel human metabolic reactions such as of the fate of iduronic acid following glycan degradation and of N-acetylglutamate in amino acid metabolism. Conclusions The results demonstrate how metabolic models can be utilised to direct hypotheses of novel metabolic functions in human metabolism; a process that we find is heavily reliant upon manual curation and biochemical insight. The effectiveness of a systems approach for novel biochemical pathway discovery in mammals is demonstrated and steps required to tailor future gap filling algorithms to mammalian metabolic networks are proposed.

  15. Thermodynamic Significance of Human Basal Metabolism

    Institute of Scientific and Technical Information of China (English)

    WangCuncheng

    1993-01-01

    The human basal state,a non-equilibrium steady state,is analysed in this paper in the light of the First and Second Laws of Thermodynamics whereby the thermodynamic significance of the basal metabolic rate and its distinction to the dissipation function and exergy loss are identified.The analysis demonstrates the correct expression of the effects of the blood flow on the heat balance in a human-body bio-heat model and the relationship between the basal metabolic rate and the blood perfusion.

  16. Metabolic disruption identified in the Huntington's disease transgenic sheep model.

    Science.gov (United States)

    Handley, Renee R; Reid, Suzanne J; Patassini, Stefano; Rudiger, Skye R; Obolonkin, Vladimir; McLaughlan, Clive J; Jacobsen, Jessie C; Gusella, James F; MacDonald, Marcy E; Waldvogel, Henry J; Bawden, C Simon; Faull, Richard L M; Snell, Russell G

    2016-02-11

    Huntington's disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissue-specificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease.

  17. The Intestinal Microbiota in Metabolic Disease

    Directory of Open Access Journals (Sweden)

    Anni Woting

    2016-04-01

    Full Text Available Gut bacteria exert beneficial and harmful effects in metabolic diseases as deduced from the comparison of germfree and conventional mice and from fecal transplantation studies. Compositional microbial changes in diseased subjects have been linked to adiposity, type 2 diabetes and dyslipidemia. Promotion of an increased expression of intestinal nutrient transporters or a modified lipid and bile acid metabolism by the intestinal microbiota could result in an increased nutrient absorption by the host. The degradation of dietary fiber and the subsequent fermentation of monosaccharides to short-chain fatty acids (SCFA is one of the most controversially discussed mechanisms of how gut bacteria impact host physiology. Fibers reduce the energy density of the diet, and the resulting SCFA promote intestinal gluconeogenesis, incretin formation and subsequently satiety. However, SCFA also deliver energy to the host and support liponeogenesis. Thus far, there is little knowledge on bacterial species that promote or prevent metabolic disease. Clostridium ramosum and Enterococcus cloacae were demonstrated to promote obesity in gnotobiotic mouse models, whereas bifidobacteria and Akkermansia muciniphila were associated with favorable phenotypes in conventional mice, especially when oligofructose was fed. How diet modulates the gut microbiota towards a beneficial or harmful composition needs further research. Gnotobiotic animals are a valuable tool to elucidate mechanisms underlying diet–host–microbe interactions.

  18. APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons

    Directory of Open Access Journals (Sweden)

    Steven Moore

    2015-05-01

    Full Text Available Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD. To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons.

  19. Glutathione Metabolism and Parkinson’s Disease

    Science.gov (United States)

    Smeyne, Michelle

    2013-01-01

    It has been established that oxidative stress, defined as the condition when the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson’s disease. Glutathione is a ubiquitous thiol tripeptide that acts alone, or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals and peroxynitrites. In this review, we examine the synthesis, metabolism and functional interactions of glutathione, and discuss how this relates to protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson’s disease. PMID:23665395

  20. Bisphenol A and Metabolic Diseases: Challenges for Occupational Medicine.

    Science.gov (United States)

    Caporossi, Lidia; Papaleo, Bruno

    2017-08-25

    The prevalence of metabolic diseases has markedly increased worldwide during the last few decades. Lifestyle factors (physical activity, energy-dense diets), together with a genetic predisposition, are well known factors in the pathophysiology of health problems. Bisphenol A (BPA) is a chemical compound used for polycarbonate plastics, food containers, epoxy resins coating metallic cans for food and beverage conservation. The ability of BPA to act as an endocrine disruptor-xenoestrogen in particular-is largely documented in literature, with numerous publications of in vivo and in vitro studies as well as epidemiological data on humans. Recently, different researchers studied the involvement of BPA in the development of insulin resistance; evidences in this way showed a potential role in etiology of metabolic disease, both for children and for adults. We review the epidemiological literature in the relation between BPA exposure and the risk of metabolic diseases in adults, with a focus on occupational exposure. Considering published data and the role of occupational physicians in promoting Workers' Health, specific situations of exposure to BPA in workplace are described, and proposals for action to be taken are suggested. The comparison of the studies showed that exposure levels were higher in workers than in the general population, even if, sometimes, the measurement units used did not permit rapid comprehension. Nevertheless, occupational medicine focus on reproductive effects and not metabolic ones.

  1. The emerging use of zebrafish to model metabolic disease

    Directory of Open Access Journals (Sweden)

    Asha Seth

    2013-09-01

    Full Text Available The zebrafish research community is celebrating! The zebrafish genome has recently been sequenced, the Zebrafish Mutation Project (launched by the Wellcome Trust Sanger Institute has published the results of its first large-scale ethylnitrosourea (ENU mutagenesis screen, and a host of new techniques, such as the genome editing technologies TALEN and CRISPR-Cas, are enabling specific mutations to be created in model organisms and investigated in vivo. The zebrafish truly seems to be coming of age. These powerful resources invoke the question of whether zebrafish can be increasingly used to model human disease, particularly common, chronic diseases of metabolism such as obesity and type 2 diabetes. In recent years, there has been considerable success, mainly from genomic approaches, in identifying genetic variants that are associated with these conditions in humans; however, mechanistic insights into the role of implicated disease loci are lacking. In this Review, we highlight some of the advantages and disadvantages of zebrafish to address the organism’s utility as a model system for human metabolic diseases.

  2. metabolicMine: an integrated genomics, genetics and proteomics data warehouse for common metabolic disease research.

    Science.gov (United States)

    Lyne, Mike; Smith, Richard N; Lyne, Rachel; Aleksic, Jelena; Hu, Fengyuan; Kalderimis, Alex; Stepan, Radek; Micklem, Gos

    2013-01-01

    Common metabolic and endocrine diseases such as diabetes affect millions of people worldwide and have a major health impact, frequently leading to complications and mortality. In a search for better prevention and treatment, there is ongoing research into the underlying molecular and genetic bases of these complex human diseases, as well as into the links with risk factors such as obesity. Although an increasing number of relevant genomic and proteomic data sets have become available, the quantity and diversity of the data make their efficient exploitation challenging. Here, we present metabolicMine, a data warehouse with a specific focus on the genomics, genetics and proteomics of common metabolic diseases. Developed in collaboration with leading UK metabolic disease groups, metabolicMine integrates data sets from a range of experiments and model organisms alongside tools for exploring them. The current version brings together information covering genes, proteins, orthologues, interactions, gene expression, pathways, ontologies, diseases, genome-wide association studies and single nucleotide polymorphisms. Although the emphasis is on human data, key data sets from mouse and rat are included. These are complemented by interoperation with the RatMine rat genomics database, with a corresponding mouse version under development by the Mouse Genome Informatics (MGI) group. The web interface contains a number of features including keyword search, a library of Search Forms, the QueryBuilder and list analysis tools. This provides researchers with many different ways to analyse, view and flexibly export data. Programming interfaces and automatic code generation in several languages are supported, and many of the features of the web interface are available through web services. The combination of diverse data sets integrated with analysis tools and a powerful query system makes metabolicMine a valuable research resource. The web interface makes it accessible to first

  3. The complement system in human cardiometabolic disease.

    Science.gov (United States)

    Hertle, E; Stehouwer, C D A; van Greevenbroek, M M J

    2014-10-01

    The complement system has been implicated in obesity, fatty liver, diabetes and cardiovascular disease (CVD). Complement factors are produced in adipose tissue and appear to be involved in adipose tissue metabolism and local inflammation. Thereby complement links adipose tissue inflammation to systemic metabolic derangements, such as low-grade inflammation, insulin resistance and dyslipidaemia. Furthermore, complement has been implicated in pathophysiological mechanisms of diet- and alcohol induced liver damage, hyperglycaemia, endothelial dysfunction, atherosclerosis and fibrinolysis. In this review, we summarize current evidence on the role of the complement system in several processes of human cardiometabolic disease. C3 is the central component in complement activation, and has most widely been studied in humans. C3 concentrations are associated with insulin resistance, liver dysfunction, risk of the metabolic syndrome, type 2 diabetes and CVD. C3 can be activated by the classical, the lectin and the alternative pathway of complement activation; and downstream activation of C3 activates the terminal pathway. Complement may also be activated via extrinsic proteases of the coagulation, fibrinolysis and the kinin systems. Studies on the different complement activation pathways in human cardiometabolic disease are limited, but available evidence suggests that they may have distinct roles in processes underlying cardiometabolic disease. The lectin pathway appeared beneficial in some studies on type 2 diabetes and CVD, while factors of the classical and the alternative pathway were related to unfavourable cardiometabolic traits. The terminal complement pathway was also implicated in insulin resistance and liver disease, and appears to have a prominent role in acute and advanced CVD. The available human data suggest a complex and potentially causal role for the complement system in human cardiometabolic disease. Further, preferably longitudinal studies are needed to

  4. The gut microbiota and metabolic disease

    DEFF Research Database (Denmark)

    Arora, T; Bäckhed, Gert Fredrik

    2016-01-01

    The human gut microbiota has been studied for more than a century. However, of nonculture-based techniques exploiting next-generation sequencing for analysing the microbiota, development has renewed research within the field during the past decade. The observation that the gut microbiota......, as an environmental factor, contributes to adiposity has further increased interest in the field. The human microbiota is affected by the diet, and macronutrients serve as substrates for many microbially produced metabolites, such as short-chain fatty acids and bile acids, that may modulate host metabolism. Obesity......-producing bacteria might be causally linked to type 2 diabetes. Bariatric surgery, which promotes long-term weight loss and diabetes remission, alters the gut microbiota in both mice and humans. Furthermore, by transferring the microbiota from postbariatric surgery patients to mice, it has been demonstrated...

  5. APP metabolism regulates tau proteostasis in human cerebral cortex neurons

    OpenAIRE

    Steven Moore; Evans, Lewis D.B.; Therese Andersson; Erik Portelius; James Smith; Tatyana B. Dias; Nathalie Saurat; Amelia McGlade; Peter Kirwan; Kaj Blennow; John Hardy; Henrik Zetterberg; Frederick J. Livesey

    2015-01-01

    This is the final version. It was first published by Elsevier at http://www.sciencedirect.com/science/article/pii/S2211124715003599. Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, a...

  6. The metabolic syndrome: a brain disease?

    Science.gov (United States)

    Buijs, Ruud M; Kreier, Felix

    2006-09-01

    The incidence of obesity with, as consequence, a rise in associated diseases such as diabetes, hypertension and dyslipidemia--the metabolic syndrome--is reaching epidemic proportions in industrialized countries. Here, we provide a hypothesis that the biological clock which normally prepares us each morning for the coming activity period is altered due to a modern life style of low activity during the day and late-night food intake. Furthermore, we review the anatomical evidence supporting the proposal that an unbalanced autonomic nervous system output may lead to the simultaneous occurrence of diabetes type 2, dyslipidemia, hypertension and visceral obesity.

  7. [Nutritional and metabolic aspects of neurological diseases].

    Science.gov (United States)

    Planas Vilà, Mercè

    2014-01-01

    The central nervous system regulates food intake, homoeostasis of glucose and electrolytes, and starts the sensations of hunger and satiety. Different nutritional factors are involved in the pathogenesis of several neurological diseases. Patients with acute neurological diseases (traumatic brain injury, cerebral vascular accident hemorrhagic or ischemic, spinal cord injuries, and cancer) and chronic neurological diseases (Alzheimer's Disease and other dementias, amyotrophic lateral sclerosis, Parkinson's Disease) increase the risk of malnutrition by multiple factors related to nutrient ingestion, abnormalities in the energy expenditure, changes in eating behavior, gastrointestinal changes, and by side effects of drugs administered. Patients with acute neurological diseases have in common the presence of hyper metabolism and hyper catabolism both associated to a period of prolonged fasting mainly for the frequent gastrointestinal complications, many times as a side effect of drugs administered. During the acute phase, spinal cord injuries presented a reduction in the energy expenditure but an increase in the nitrogen elimination. In order to correct the negative nitrogen balance increase intakes is performed with the result of a hyper alimentation that should be avoided due to the complications resulting. In patients with chronic neurological diseases and in the acute phase of cerebrovascular accident, dysphagia could be present which also affects intakes. Several chronic neurological diseases have also dementia, which lead to alterations in the eating behavior. The presence of malnutrition complicates the clinical evolution, increases muscular atrophy with higher incidence of respiratory failure and less capacity to disphagia recuperation, alters the immune response with higher rate of infections, increases the likelihood of fractures and of pressure ulcers, increases the incapacity degree and is an independent factor to increase mortality. The periodic nutritional

  8. Genome-scale modeling of human metabolism - a systems biology approach.

    Science.gov (United States)

    Mardinoglu, Adil; Gatto, Francesco; Nielsen, Jens

    2013-09-01

    Altered metabolism is linked to the appearance of various human diseases and a better understanding of disease-associated metabolic changes may lead to the identification of novel prognostic biomarkers and the development of new therapies. Genome-scale metabolic models (GEMs) have been employed for studying human metabolism in a systematic manner, as well as for understanding complex human diseases. In the past decade, such metabolic models - one of the fundamental aspects of systems biology - have started contributing to the understanding of the mechanistic relationship between genotype and phenotype. In this review, we focus on the construction of the Human Metabolic Reaction database, the generation of healthy cell type- and cancer-specific GEMs using different procedures, and the potential applications of these developments in the study of human metabolism and in the identification of metabolic changes associated with various disorders. We further examine how in silico genome-scale reconstructions can be employed to simulate metabolic flux distributions and how high-throughput omics data can be analyzed in a context-dependent fashion. Insights yielded from this mechanistic modeling approach can be used for identifying new therapeutic agents and drug targets as well as for the discovery of novel biomarkers. Finally, recent advancements in genome-scale modeling and the future challenge of developing a model of whole-body metabolism are presented. The emergent contribution of GEMs to personalized and translational medicine is also discussed. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Lactate metabolism in chronic liver disease

    DEFF Research Database (Denmark)

    Jeppesen, Johanne B; Mortensen, Christian; Bendtsen, Flemming

    2013-01-01

    Background. In the healthy liver there is a splanchnic net-uptake of lactate caused by gluconeogenesis. It has previously been shown that patients with acute liver failure in contrast have a splanchnic release of lactate caused by a combination of accelerated glycolysis in the splanchnic region...... and a reduction in hepatic gluconeogenesis. Aims. The aims of the present study were to investigate lactate metabolism and kinetics in patients with chronic liver disease compared with a control group with normal liver function. Methods. A total of 142 patients with chronic liver disease and 14 healthy controls...... underwent a liver vein catheterization. Blood samples from the femoral artery and the hepatic and renal veins were simultaneously collected before and after stimulation with galactose. Results. The fasting lactate levels, both in the hepatic vein and in the femoral artery, were higher in the patients than...

  10. Can we prevent obesity-related metabolic diseases by dietary modulation of the gut microbiota?

    DEFF Research Database (Denmark)

    Brahe, Lena Kirchner; Astrup, Arne; Larsen, Lesli Hingstrup

    2016-01-01

    Obesity increases the risk of type 2 diabetes, cardiovascular diseases, and certain cancers, which are among the leading causes of death worldwide. Obesity and obesity-related metabolic diseases are characterized by specific alterations in the human gut microbiota. Experimental studies with gut...... microbiota transplantations in mice and in humans indicate that a specific gut microbiota composition can be the cause and not just the consequence of the obese state and metabolic disease, which suggests a potential for gut microbiota modulation in prevention and treatment of obesity-related metabolic...... diseases. In addition, dietary intervention studies have suggested that modulation of the gut microbiota can improve metabolic risk markers in humans, but a causal role of the gut microbiota in such studies has not yet been established. Here, we review and discuss the role of the gut microbiota in obesity...

  11. Genetic Mapping in Human Disease

    OpenAIRE

    Altshuler, David; Daly, Mark J; Lander, Eric S.

    2008-01-01

    Genetic mapping provides a powerful approach to identify genes and biological processes underlying any trait influenced by inheritance, including human diseases. We discuss the intellectual foundations of genetic mapping of Mendelian and complex traits in humans, examine lessons emerging from linkage analysis of Mendelian diseases and genome-wide association studies of common diseases, and discuss questions and challenges that lie ahead.

  12. Adipokines, metabolic syndrome and rheumatic diseases.

    Science.gov (United States)

    Abella, Vanessa; Scotece, Morena; Conde, Javier; López, Verónica; Lazzaro, Verónica; Pino, Jesús; Gómez-Reino, Juan J; Gualillo, Oreste

    2014-01-01

    The metabolic syndrome (MetS) is a cluster of cardiometabolic disorders that result from the increasing prevalence of obesity. The major components of MetS include insulin resistance, central obesity, dyslipidemia, and hypertension. MetS identifies the central obesity with increased risk for cardiovascular diseases (CVDs) and type-2 diabetes mellitus (T2DM). Patients with rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis, have increased prevalence of CVDs. Moreover, CVD risk is increased when obesity is present in these patients. However, traditional cardiovascular risk factors do not completely explain the enhanced cardiovascular risk in this population. Thus, MetS and the altered secretion patterns of proinflammatory adipokines present in obesity could be the link between CVDs and rheumatic diseases. Furthermore, adipokines have been linked to the pathogenesis of MetS and its comorbidities through their effects on vascular function and inflammation. In the present paper, we review recent evidence of the role played by adipokines in the modulation of MetS in the general population, and in patients with rheumatic diseases.

  13. Adipokines, Metabolic Syndrome and Rheumatic Diseases

    Directory of Open Access Journals (Sweden)

    Vanessa Abella

    2014-01-01

    Full Text Available The metabolic syndrome (MetS is a cluster of cardiometabolic disorders that result from the increasing prevalence of obesity. The major components of MetS include insulin resistance, central obesity, dyslipidemia, and hypertension. MetS identifies the central obesity with increased risk for cardiovascular diseases (CVDs and type-2 diabetes mellitus (T2DM. Patients with rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis, have increased prevalence of CVDs. Moreover, CVD risk is increased when obesity is present in these patients. However, traditional cardiovascular risk factors do not completely explain the enhanced cardiovascular risk in this population. Thus, MetS and the altered secretion patterns of proinflammatory adipokines present in obesity could be the link between CVDs and rheumatic diseases. Furthermore, adipokines have been linked to the pathogenesis of MetS and its comorbidities through their effects on vascular function and inflammation. In the present paper, we review recent evidence of the role played by adipokines in the modulation of MetS in the general population, and in patients with rheumatic diseases.

  14. Nutrigenomic programming of cardiovascular and metabolic diseases.

    Science.gov (United States)

    Ozanne, Susan

    2014-10-01

    Over twenty five years ago epidemiological studies revealed that there was a relationship between patterns of early growth and subsequent risk of diseases such as type 2 diabetes, cardiovascular disease and the metabolic syndrome. Studies of identical twins, individuals who were in utero during periods of famine, discordant siblings and animal models have provided strong evidence that the early environment plays an important role in mediating these relationships. Early nutrition is one such important environmental factor. The concept of early life programming is therefore widely accepted and the underlying mechanisms starting to emerge. These include: (1) Permanent structural changes in an organ due to exposure to suboptimal levels of essential hormones or nutrients during a critical period of development leading to permanent changes in tissue function (2) Persistent epigenetic changes such as DNA methylation and histone modifications and miRNAs leading to changes in gene expression. (3) Permanent effects on regulation of cellular ageing through increases in oxidative stress and mitochondrial dysfunction leading to DNA damage and telomere shortening. Further understanding of these processes will enable the development of preventative and intervention strategies to combat the burden of common diseases such as type 2 diabetes and cardiovascular disease.

  15. Evolution of Microbial Quorum Sensing to Human Global Quorum Sensing: An Insight into How Gap Junctional Intercellular Communication Might Be Linked to the Global Metabolic Disease Crisis.

    Science.gov (United States)

    Trosko, James E

    2016-06-15

    The first anaerobic organism extracted energy for survival and reproduction from its source of nutrients, with the genetic means to ensure protection of its individual genome but also its species survival. While it had a means to communicate with its community via simple secreted molecules ("quorum sensing"), the eventual shift to an aerobic environment led to multi-cellular metazoan organisms, with evolutionary-selected genes to form extracellular matrices, stem cells, stem cell niches, and a family of gap junction or "connexin" genes. These germinal and somatic stem cells responded to extracellular signals that triggered intra-cellular signaling to regulate specific genes out of the total genome. These extra-cellular induced intra-cellular signals also modulated gap junctional intercellular communication (GJIC) in order to regulate the new cellular functions of symmetrical and asymmetrical cell division, cell differentiation, modes of cell death, and senescence. Within the hierarchical and cybernetic concepts, differentiated by neurons organized in the brain of the Homo sapiens, the conscious mind led to language, abstract ideas, technology, myth-making, scientific reasoning, and moral decision-making, i.e., the creation of culture. Over thousands of years, this has created the current collision between biological and cultural evolution, leading to the global "metabolic disease" crisis.

  16. Celiac disease: A missed cause of metabolic bone disease

    Directory of Open Access Journals (Sweden)

    Ashu Rastogi

    2012-01-01

    Full Text Available Introduction: Celiac disease (CD is a highly prevalent autoimmune disease. The symptoms of CD are varied and atypical, with many patients having no gastrointestinal symptoms. Metabolic bone disease (MBD is a less recognized manifestation of CD associated with spectrum of musculoskeletal signs and symptoms, viz. bone pains, proximal muscle weakness, osteopenia, osteoporosis, and fracture. We here report five patients who presented with severe MBD as the only manifestation of CD. Materials and Methods: Records of 825 patients of CD diagnosed during 2002-2010 were retrospectively analyzed for clinical features, risk factors, signs, biochemical, and radiological parameters. Results: We were able to identify five patients (0.6% of CD who had monosymptomatic presentation with musculoskeletal symptoms and signs in the form of bone pains, proximal myopathy, and fragility fractures without any gastrointestinal manifestation. All the five patients had severe MBD in the form of osteopenia, osteoporosis, and fragility fractures. Four of the five patients had additional risk factors such as antiepileptic drugs, chronic alcohol consumption, malnutrition, and associated vitamin D deficiency which might have contributed to the severity of MBD. Conclusion: Severe metabolic disease as the only presentation of CD is rare. Patients show significant improvement in clinical, biochemical, and radiological parameters with gluten-free diet, calcium, and vitamin D supplementation. CD should be looked for routinely in patients presenting with unexplained MBD.

  17. The human hepatocyte cell lines IHH and HepaRG : models to study glucose, lipid and lipoprotein metabolism

    NARCIS (Netherlands)

    Samanez, Carolina Huaman; Caron, Sandrine; Briand, Olivier; Dehondt, Helene; Duplan, Isabelle; Kuipers, Folkert; Hennuyer, Nathalie; Clavey, Veronique; Staels, Bart

    2012-01-01

    Metabolic diseases reach epidemic proportions. A better knowledge of the associated alterations in the metabolic pathways in the liver is necessary. These studies need in vitro human cell models. Several human hepatoma models are used, but the response of many metabolic pathways to physiological sti

  18. The human hepatocyte cell lines IHH and HepaRG : models to study glucose, lipid and lipoprotein metabolism

    NARCIS (Netherlands)

    Samanez, Carolina Huaman; Caron, Sandrine; Briand, Olivier; Dehondt, Helene; Duplan, Isabelle; Kuipers, Folkert; Hennuyer, Nathalie; Clavey, Veronique; Staels, Bart

    Metabolic diseases reach epidemic proportions. A better knowledge of the associated alterations in the metabolic pathways in the liver is necessary. These studies need in vitro human cell models. Several human hepatoma models are used, but the response of many metabolic pathways to physiological

  19. Discovery of Infection Associated Metabolic Markers in Human African Trypanosomiasis.

    Science.gov (United States)

    Lamour, Sabrina D; Gomez-Romero, Maria; Vorkas, Panagiotis A; Alibu, Vincent P; Saric, Jasmina; Holmes, Elaine; Sternberg, Jeremy M

    2015-01-01

    Human African trypanosomiasis (HAT) remains a major neglected tropical disease in Sub-Saharan Africa. As clinical symptoms are usually non-specific, new diagnostic and prognostic markers are urgently needed to enhance the number of identified cases and optimise treatment. This is particularly important for disease caused by Trypanosoma brucei rhodesiense, where indirect immunodiagnostic approaches have to date been unsuccessful. We have conducted global metabolic profiling of plasma from T.b.rhodesiense HAT patients and endemic controls, using 1H nuclear magnetic resonance (NMR) spectroscopy and ultra-performance liquid chromatography, coupled with mass spectrometry (UPLC-MS) and identified differences in the lipid, amino acid and metabolite profiles. Altogether 16 significantly disease discriminatory metabolite markers were found using NMR, and a further 37 lipid markers via UPLC-MS. These included significantly higher levels of phenylalanine, formate, creatinine, N-acetylated glycoprotein and triglycerides in patients relative to controls. HAT patients also displayed lower concentrations of histidine, sphingomyelins, lysophosphatidylcholines, and several polyunsaturated phosphatidylcholines. While the disease metabolite profile was partially consistent with previous data published in experimental rodent infection, we also found unique lipid and amino acid profile markers highlighting subtle but important differences between the host response to trypanosome infections between animal models and natural human infections. Our results demonstrate the potential of metabolic profiling in the identification of novel diagnostic biomarkers and the elucidation of pathogenetic mechanisms in this disease.

  20. Metabolic diseases and pro- and prebiotics: Mechanistic insights

    OpenAIRE

    Nakamura Yukiko K; Omaye Stanley T

    2012-01-01

    Abstract Metabolic diseases, such as obesity and type 2 diabetes, are world-wide health problems. The prevalence of metabolic diseases is associated with dynamic changes in dietary macronutrient intake during the past decades. Based on national statistics and from a public health viewpoint, traditional approaches, such as diet and physical activity, have been unsuccessful in decreasing the prevalence of metabolic diseases. Since the approaches strongly rely on individual’s behavior and motiva...

  1. Leukocyte set points in metabolic disease.

    Science.gov (United States)

    Odegaard, Justin I; Chawla, Ajay

    2012-01-01

    Vertebrate tissues comprise precise admixtures of parenchymal and hematopoietic cells, whose interactions are vital to proper tissue function. By regulating this interaction, vertebrates are able to mitigate environmental stress and coordinate dramatic physiologic adaptations. For instance, under conditions of chronic nutrient excess, leukocyte recruitment and activation increase in an effort to decrease excess nutrient storage and alleviate adipocyte stress. While basal equilibria may be reestablished upon normalization of nutrient intake, a new set point characterized by insulin resistance and chronic inflammation is established if the stress persists. Consequently, although this response is adaptive in settings of acute overfeeding and infection, it has catastrophic health consequences in the modern context of obesity. Understanding how leukocyte set points (numbers and activation status) are established, maintained, and regulated in tissues is, thus, critical to our understanding of, and intervention in, chronic metabolic diseases, such as obesity and diabetes.

  2. Disorders of Iron Metabolism and Anemia in Chronic Kidney Disease.

    Science.gov (United States)

    Panwar, Bhupesh; Gutiérrez, Orlando M

    2016-07-01

    Dysregulated iron homeostasis plays a central role in the development of anemia of chronic kidney disease (CKD) and is a major contributor toward resistance to treatment with erythropoiesis-stimulating agents. Understanding the underlying pathophysiology requires an in-depth understanding of normal iron physiology and regulation. Recent discoveries in the field of iron biology have greatly improved our understanding of the hormonal regulation of iron trafficking in human beings and how its alterations lead to the development of anemia of CKD. In addition, emerging evidence has suggested that iron homeostasis interacts with bone and mineral metabolism on multiple levels, opening up new avenues of investigation into the genesis of disordered iron metabolism in CKD. Building on recent advances in our understanding of normal iron physiology and abnormalities in iron homeostasis in CKD, this review characterizes how anemia related to disordered iron metabolism develops in the setting of CKD. In addition, this review explores our emerging recognition of the connections between iron homeostasis and mineral metabolism and their implications for the management of altered iron status and anemia of CKD.

  3. Metatranscriptomics of the human oral microbiome during health and disease.

    Science.gov (United States)

    Jorth, Peter; Turner, Keith H; Gumus, Pinar; Nizam, Nejat; Buduneli, Nurcan; Whiteley, Marvin

    2014-04-01

    The human microbiome plays important roles in health, but when disrupted, these same indigenous microbes can cause disease. The composition of the microbiome changes during the transition from health to disease; however, these changes are often not conserved among patients. Since microbiome-associated diseases like periodontitis cause similar patient symptoms despite interpatient variability in microbial community composition, we hypothesized that human-associated microbial communities undergo conserved changes in metabolism during disease. Here, we used patient-matched healthy and diseased samples to compare gene expression of 160,000 genes in healthy and diseased periodontal communities. We show that health- and disease-associated communities exhibit defined differences in metabolism that are conserved between patients. In contrast, the metabolic gene expression of individual species was highly variable between patients. These results demonstrate that despite high interpatient variability in microbial composition, disease-associated communities display conserved metabolic profiles that are generally accomplished by a patient-specific cohort of microbes. IMPORTANCE The human microbiome project has shown that shifts in our microbiota are associated with many diseases, including obesity, Crohn's disease, diabetes, and periodontitis. While changes in microbial populations are apparent during these diseases, the species associated with each disease can vary from patient to patient. Taking into account this interpatient variability, we hypothesized that specific microbiota-associated diseases would be marked by conserved microbial community behaviors. Here, we use gene expression analyses of patient-matched healthy and diseased human periodontal plaque to show that microbial communities have highly conserved metabolic gene expression profiles, whereas individual species within the community do not. Furthermore, disease-associated communities exhibit conserved changes

  4. Metabolic Signatures of Exercise in Human Plasma

    Science.gov (United States)

    Lewis, Gregory D.; Farrell, Laurie; Wood, Malissa J.; Martinovic, Maryann; Arany, Zoltan; Rowe, Glenn C; Souza, Amanda; Cheng, Susan; McCabe, Elizabeth L.; Yang, Elaine; Shi, Xu; Deo, Rahul; Roth, Frederick P.; Asnani, Aarti; Rhee, Eugene P.; Systrom, David M.; Semigran, Marc J.; Vasan, Ramachandran S.; Carr, Steven A.; Wang, Thomas J.; Sabatine, Marc S.; Clish, Clary B.; Gerszten, Robert E.

    2010-01-01

    Exercise provides numerous salutary effects, but our understanding of how these occur is limited. To gain a clearer picture of exercise-induced metabolic responses, we have developed comprehensive plasma metabolite signatures by using mass spectrometry to measure over 200 metabolites before and after exercise. We identified plasma indicators of glycogenolysis (glucose-6-phosphate), tricarboxylic acid (TCA) cycle span 2 expansion (succinate, malate, and fumarate), and lipolysis (glycerol), as well as modulators of insulin sensitivity (niacinamide) and fatty acid oxidation (pantothenic acid). Metabolites that were highly correlated with fitness parameters were found in subjects undergoing acute exercise testing, marathon running, and in 302 subjects from a longitudinal cohort study. Exercise-induced increases in glycerol were strongly related to fitness levels in normal individuals and were attenuated in subjects with myocardial ischemia. A combination of metabolites that increased in plasma in response to exercise (glycerol, niacinamide, glucose-6-phosphate, pantothenate, and succinate) upregulated the expression of nur77, a transcriptional regulator of glucose utilization and lipid metabolism genes in skeletal muscle. Plasma metabolic profiles obtained during exercise provide signatures of exercise performance and cardiovascular disease susceptibility, in addition to highlighting molecular pathways that may modulate the salutary effects of exercise. PMID:20505214

  5. Computational Modeling of Human Metabolism and Its Application to Systems Biomedicine.

    Science.gov (United States)

    Aurich, Maike K; Thiele, Ines

    2016-01-01

    Modern high-throughput techniques offer immense opportunities to investigate whole-systems behavior, such as those underlying human diseases. However, the complexity of the data presents challenges in interpretation, and new avenues are needed to address the complexity of both diseases and data. Constraint-based modeling is one formalism applied in systems biology. It relies on a genome-scale reconstruction that captures extensive biochemical knowledge regarding an organism. The human genome-scale metabolic reconstruction is increasingly used to understand normal cellular and disease states because metabolism is an important factor in many human diseases. The application of human genome-scale reconstruction ranges from mere querying of the model as a knowledge base to studies that take advantage of the model's topology and, most notably, to functional predictions based on cell- and condition-specific metabolic models built based on omics data.An increasing number and diversity of biomedical questions are being addressed using constraint-based modeling and metabolic models. One of the most successful biomedical applications to date is cancer metabolism, but constraint-based modeling also holds great potential for inborn errors of metabolism or obesity. In addition, it offers great prospects for individualized approaches to diagnostics and the design of disease prevention and intervention strategies. Metabolic models support this endeavor by providing easy access to complex high-throughput datasets. Personalized metabolic models have been introduced. Finally, constraint-based modeling can be used to model whole-body metabolism, which will enable the elucidation of metabolic interactions between organs and disturbances of these interactions as either causes or consequence of metabolic diseases. This chapter introduces constraint-based modeling and describes some of its contributions to systems biomedicine.

  6. Periodontal disease: the influence of metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Marchetti Enrico

    2012-09-01

    Full Text Available Abstract Metabolic syndrome (MetS is a cluster of cardiovascular risk factors that include obesity, impaired glucose tolerance or diabetes, hyperinsulinemia, hypertension, and dyslipidemia. Recently, more attention has been reserved to the correlation between periodontitis and systemic health. MetS is characterized by oxidative stress, a condition in which the equilibrium between the production and the inactivation of reactive oxygen species (ROS becomes disrupted. ROS have an essential role in a variety of physiological systems, but under a condition of oxidative stress, they contribute to cellular dysfunction and damage. Oxidative stress may act as a common link to explain the relationship between each component of MetS and periodontitis. All those conditions show increased serum levels of products derived from oxidative damage, promoting a proinflammatory state. Moreover, adipocytokines, produced by the fat cells of fat tissue, might modulate the balance between oxidant and antioxidant activities. An increased caloric intake involves a higher metabolic activity, which results in an increased production of ROS, inducing insulin resistance. At the same time, obese patients require more insulin to maintain blood glucose homeostasis – a state known as hyperinsulinemia, a condition that can evolve into type 2 diabetes. Oxidation products can increase neutrophil adhesion and chemotaxis, thus favoring oxidative damage. Hyperglycemia and an oxidizing state promote the genesis of advanced glycation end-products, which could also be implicated in the degeneration and damage of periodontal tissue. Thus, MetS, the whole of interconnected factors, presents systemic and local manifestations, such as cardiovascular disease and periodontitis, related by a common factor known as oxidative stress.

  7. Visfatin, glucose metabolism and vascular disease: a review of evidence

    Directory of Open Access Journals (Sweden)

    Saddi-Rosa Pedro

    2010-03-01

    Full Text Available Abstract The adipose tissue is an endocrine organ producing substances called adipocytokines that have different effects on lipid metabolism, metabolic syndrome, and cardiovascular risk. Visfatin was recently described as an adipocytokine with potentially important effects on glucose metabolism and atherosclerosis. Visfatin has been linked to several inflammatory conditions, beta cell function, and cardiovascular disease. The growing number of publications on the subject shall bring further evidence about this adipocytokine. Its findings may contribute in the identification of higher risk individuals for diabetes and cardiovascular disease with a better comprehension about the complex intercorrelation between adiposity, glucose metabolism and vascular disease.

  8. MODERN LIFE AND NEW DISEASES: METABOLIC SYNDROME

    Directory of Open Access Journals (Sweden)

    Ahmet KORKMAZ

    2006-08-01

    Full Text Available Although modern human genome remained relatively constant, the profound changes in its environment has been appeared. Genome are needed time to adapt these changes and at this point, the discordance leed the problem which have high mortality, morbidity, so-called “diseases of civilisation”. Some of the main changes occurred in environment are daily lifestyle conditions and dietary habits. These changes has started with industrial revolution and hastened with 20th century. If the environmental changes is accepted to continue, it is clear to understand that “diseases of civilisation” remain as a serious public health problem in front of us. This problem is not only for industrialized Western civilitasion but also for our country that continue to industrialize. [TAF Prev Med Bull 2006; 5(4.000: 307-316

  9. NLRP3 inflammasomes link inflammation and metabolic disease

    OpenAIRE

    De Nardo, Dominic; Latz, Eicke

    2011-01-01

    A strong link between inflammation and metabolism is becoming increasingly evident. A number of recent landmark studies have implicated the activation of the NLRP3 inflammasome, an interleukin-1β family cytokine-activating protein complex, in a variety of metabolic diseases including obesity, atherosclerosis and type 2 diabetes. Here we review these new developments and discuss their implications for better understanding inflammation in metabolic disease and the prospects of targeting the NLR...

  10. NLRP3 inflammasomes link inflammation and metabolic disease.

    Science.gov (United States)

    De Nardo, Dominic; Latz, Eicke

    2011-08-01

    A strong link between inflammation and metabolism is becoming increasingly evident. A number of recent landmark studies have implicated the activation of the NLRP3 inflammasome, an interleukin-1β family cytokine-activating protein complex, in a variety of metabolic diseases including obesity, atherosclerosis and type 2 diabetes. Here, we review these new developments and discuss their implications for a better understanding of inflammation in metabolic disease, and the prospects of targeting the NLRP3 inflammasome for therapeutic intervention.

  11. Using skin to assess iron accumulation in human metabolic disorders

    Energy Technology Data Exchange (ETDEWEB)

    Guinote, I. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. 10, 2685-953 Sacavem (Portugal); Fleming, R. [Imunohaemotherapy Department, Hospital de St. Maria, Lisbon (Portugal); Silva, R. [Dermatology Department, Hospital de St. Maria, Lisbon (Portugal); Filipe, P. [Dermatology Department, Hospital de St. Maria, Lisbon (Portugal); Silva, J.N. [Dermatology Department, Hospital de St. Maria, Lisbon (Portugal); Verissimo, A. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. 10, 2685-953 Sacavem (Portugal); Napoleao, P. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. 10, 2685-953 Sacavem (Portugal); Centro de Fisica Nuclear, Universidade de Lisbon (Portugal); Alves, L.C. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. 10, 2685-953 Sacavem (Portugal); Centro de Fisica Nuclear, Universidade de Lisbon (Portugal); Pinheiro, T. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. 10, 2685-953 Sacavem (Portugal) and Centro de Fisica Nuclear, Universidade de Lisbon (Portugal)]. E-mail: murmur@itn.pt

    2006-08-15

    The distribution of Fe in skin was assessed to monitor body Fe status in human hereditary hemochromatosis. The paper reports on data from nine patients with hemochromatosis that were studied along the therapeutic programme. Systemic evaluation of Fe metabolism was carried out by measuring with PIXE technique the Fe concentration in plasma and blood cells, and by determining with biochemical methods the indicators of Fe transport in serum (ferritin and transferrin). The Fe distribution and concentration in skin was assessed by nuclear microscopy and Fe deposits in liver estimated through nuclear magnetic resonance. Elevated Fe concentrations in skin were related to increased plasma Fe (p < 0.004), serum ferritin content (p < 0.01) and Fe deposits in liver (p < 0.004). The relationship of Fe deposits in organs and metabolism markers may help to better understand Fe pools mobilisation and to establish the quality of skin as a marker for the disease progression and therapy efficacy.

  12. Using skin to assess iron accumulation in human metabolic disorders

    Science.gov (United States)

    Guinote, I.; Fleming, R.; Silva, R.; Filipe, P.; Silva, J. N.; Veríssimo, A.; Napoleão, P.; Alves, L. C.; Pinheiro, T.

    2006-08-01

    The distribution of Fe in skin was assessed to monitor body Fe status in human hereditary hemochromatosis. The paper reports on data from nine patients with hemochromatosis that were studied along the therapeutic programme. Systemic evaluation of Fe metabolism was carried out by measuring with PIXE technique the Fe concentration in plasma and blood cells, and by determining with biochemical methods the indicators of Fe transport in serum (ferritin and transferrin). The Fe distribution and concentration in skin was assessed by nuclear microscopy and Fe deposits in liver estimated through nuclear magnetic resonance. Elevated Fe concentrations in skin were related to increased plasma Fe (p serum ferritin content (p < 0.01) and Fe deposits in liver (p < 0.004). The relationship of Fe deposits in organs and metabolism markers may help to better understand Fe pools mobilisation and to establish the quality of skin as a marker for the disease progression and therapy efficacy.

  13. Human folate metabolism using 14C-accelerator mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Clifford, A. J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Arjomand, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Duecker, S. R. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Johnson, H. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Schneider, P. D. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Zulim, R. A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Bucholz, B. A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Vogel, J. S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    1999-03-25

    Folate is a water soluble vitamin required for optimal health, growth and development. It occurs naturally in various states of oxidation of the pteridine ring and with varying lengths to its glutamate chain. Folates function as one-carbon donors through methyl transferase catalyzed reactions. Low-folate diets, especially by those with suboptimal methyltransferase activity, are associated with increased risk of neural tube birth defects in children, hyperhomocysteinemic heart disease, and cancer in adults. Rapidly dividing (neoplastic) cells have a high folate need for DNA synthesis. Chemical analogs of folate (antifolates) that interfere with folate metabolism are used as therapeutic agents in cancer treatment. Although much is known about folate chemistry, metabolism of this vitamin in vivo in humans is not well understood. Since folate levels in blood and tissues are very low and methods to measure them are inadequate, the few previous studies that have examined folate metabolism used large doses of radiolabeled folic acid in patients with Hodgkin's disease and cancer (Butterworth et al. 1969, Krumdieck et al. 1978). A subsequent protocol using deuterated folic acid was also insufficiently sensitive to trace a physiologic folate dose (Stites et al. 1997). Accelerator mass spectrometry (AMS) is an emerging bioanalytical tool that overcomes the limitations of traditional mass spectrometry and of decay counting of long lived radioisotopes (Vogel et al. 1995). AMS can detect attomolar concentrations of 14 C in milligram-sized samples enabling in vivo radiotracer studies in healthy humans. We used AMS to study the metabolism of a physiologic 80 nmol oral dose of 14 C-folic acid (1/6 US RDA) by measuring the 14 C-folate levels in serial plasma, urine and feces samples taken over a 150-day period after dosing a healthy adult volunteer.

  14. [Metabolic syndrome in inflammatory rheumatic diseases].

    Science.gov (United States)

    Malesci, D; Valentini, G; La Montagna, G

    2006-01-01

    Toward the end of the last century a better knowledge of cardiovascular (CV) risk factors and their associations led investigators to propose the existence of a unique pathophysiological condition called "metabolic" or "insulin resistance syndrome". Among all, insulin-resistance and compensatory hyperinsulinemia are considered its most important treatment targets. Different definitions have been provided by World Health Organization (WHO) and by The Third Report of The National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP III). In particular, abdominal obesity, hypertension, low HDL cholesterol and hyperglicemia are the most common items used for its definition. The presence of MetS is effective in predicting the future risk of diabetes and coronaropathies. The evidence of a higher CV risk rate among different rheumatic inflammatory diseases has recently been associated with high prevalence of MetS in some cases. Rheumatoid or psoriatic arthritis have the large series among arthritis, whereas systemic lupus erythematosus among connective tissue disorders. This review analyses all most important studies about the evidence of MetS in rheumatic patients and the main clinical and prognostic significance of this relation.

  15. Latest data on metabolic diseases: Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Panagiota Mitrou

    2017-01-01

    Full Text Available With such a high cost in money and human lives, diabetes mellitus (DM is a major challenge for health care systems and an obstacle to sustainable economic growth. The pathophysiological disorders of diabetes include, besides the defect in pancreatic insulin secretion and insulin resistance in peripheral tissues (liver, muscle and adipose tissue, increased lipolysis, increased glucagon secretion, impaired secretion and action of incretin hormones, increased glucose resorption by the kidney and defects in the central nervous system. The therapeutic intervention must be timely and personalized. Lifestyle interventions (diet, exercise, smoking cessation are the cornerstone of treatment. Treatment should begin with metformin unless there is a contraindication (eg renal failure or intolerance (eg, gastrointestinal disorders. If HbA1c remains off target a second or a third treatment may be added, orally (glitazone, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylurea or by injection (GLP-1 agonist or basal insulin. On failure to achieve glycemic target combinations of injectable treatments (combination of agonist GLP-1 with basal insulin, intensified insulin therapy or in some cases insulin mixtures are recommended. New treatments (weekly administered GLP-1 analogs, combination of a basal insulin / GLP-1 in one injection, SGLT-2 inhibitors, long acting basal insulins in combination with the old tried treatments (e.g. metformin, pioglitazone, inhibitors DPP-4 can contribute to human-centered and individualized management of patients with diabetes. The cardiovascular safety of antidiabetic treatment should be considered. There is a need for early diagnosis and treatment of glucose metabolism disorders during pregnancy (before 24 to 28 weeks of gestation in women at high risk for developing gestational diabetes.

  16. The role of chemerin in human disease

    Directory of Open Access Journals (Sweden)

    Magdalena Stojek

    2017-02-01

    Full Text Available Adipose tissue is not merely a storage depot of triacylglycerols but also a major endocrine organ. Its cells, including adipocytes, synthesize and secrete a range of biologically active molecules termed adipokines. Adipokines that display the properties of cytokines are often called adipocytokines. In recent years there has been increasing interest in a new adipokine called chemerin. Chemerin is a protein synthesized mostly by the adipose tissue and the liver as inactive pre-pro-chemerin. After the intracellular hydrolytic cutting off of the 20-amino-acid N-terminal polypeptide, it is secreted into the bloodstream as inactive pro-chemerin. Biologically active chemerin is then derived from pro-chemerin after cleavage of the C-terminal fragment by serum proteases involved in inflammation, coagulation and fibrinolysis. Proteolytic cleavage leads to formation of several chemerin-derived peptides, both biologically active (often with opposing functions and inactive.Within the last decade, there has been a growing number of publications regarding the role of chemerin in human disease. It seems to be implicated in the inflammatory response, metabolic syndrome, cardiovascular disease and alimentary tract disorders. The article presents the most recent information on the role of chemerin in human disease, and specifically alimentary tract disorders. The available evidence suggests that chemerin is an important link between adipose tissue mass, metabolic processes, the immune system and inflammation, and therefore plays a major role in human pathophysiology.

  17. Tissue Renin-Angiotensin Systems: A Unifying Hypothesis of Metabolic Disease

    Directory of Open Access Journals (Sweden)

    Jeppe eSkov

    2014-02-01

    Full Text Available The actions of angiotensin peptides are diverse and locally acting tissue renin-angiotensin systems (RAS are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g. diabetes and its complications and blockers of RAS have been demonstrated to prevent diabetes in humans.Hyperglycemia, obesity, hypertension, and cortisol are well-known risk factors of metabolic disease and all stimulate tissue RAS whereas glucagon-like peptide-1, vitamin D, and aerobic exercise are inhibitors of tissue RAS and to some extent can prevent metabolic disease. Furthermore, an activated tissue RAS deteriorates the same risk factors creating a system with several positive feedback pathways. The primary effector hormone of the RAS, angiotensin II, stimulates reactive oxygen species, induces tissue damage, and can be associated to most diabetic complications. Based on these observations we hypothesize that an activated tissue RAS is the principle cause of metabolic syndrome and type 2 diabetes, and additionally is mediating the majority of the metabolic complications. The involvement of positive feedback pathways may create a self-reinforcing state and explain why metabolic disease initiate and progress. The hypothesis plausibly unify the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control.

  18. Metabolic syndrome in rheumatic diseases: epidemiology, pathophysiology, and clinical implications.

    Science.gov (United States)

    Sidiropoulos, Prodromos I; Karvounaris, Stylianos A; Boumpas, Dimitrios T

    2008-01-01

    Subjects with metabolic syndrome--a constellation of cardiovascular risk factors of which central obesity and insulin resistance are the most characteristic--are at increased risk for developing diabetes mellitus and cardiovascular disease. In these subjects, abdominal adipose tissue is a source of inflammatory cytokines such as tumor necrosis factor-alpha, known to promote insulin resistance. The presence of inflammatory cytokines together with the well-documented increased risk for cardiovascular diseases in patients with inflammatory arthritides and systemic lupus erythematosus has prompted studies to examine the prevalence of the metabolic syndrome in an effort to identify subjects at risk in addition to that conferred by traditional cardiovascular risk factors. These studies have documented a high prevalence of metabolic syndrome which correlates with disease activity and markers of atherosclerosis. The correlation of inflammatory disease activity with metabolic syndrome provides additional evidence for a link between inflammation and metabolic disturbances/vascular morbidity.

  19. Gut microbiota and immune crosstalk in metabolic disease

    OpenAIRE

    2016-01-01

    Background: Gut microbiota is considered as a major regulator of metabolic disease. This reconciles the notion of metabolic inflammation and the epidemic development of the disease. In addition to evidence showing that a specific gut microbiota characterizes patients with obesity, type 2 diabetes, and hepatic steatosis, the mechanisms causal to the disease could be related to the translocation of microbiota from the gut to the tissues, inducing inflammation. The mechanisms regulating such a p...

  20. Metabolic Effects of Obesity and Its Interaction with Endocrine Diseases.

    Science.gov (United States)

    Clark, Melissa; Hoenig, Margarethe

    2016-09-01

    Obesity in pet dogs and cats is a significant problem in developed countries, and seems to be increasing in prevalence. Excess body fat has adverse metabolic consequences, including insulin resistance, altered adipokine secretion, changes in metabolic rate, abnormal lipid metabolism, and fat accumulation in visceral organs. Obese cats are predisposed to endocrine and metabolic disorders such as diabetes and hepatic lipidosis. A connection likely also exists between obesity and diabetes mellitus in dogs. No system has been developed to identify obese pets at greatest risk for development of obesity-associated metabolic diseases, and further study in this area is needed.

  1. Understanding the role of gut microbiome in metabolic disease risk.

    Science.gov (United States)

    Sanz, Yolanda; Olivares, Marta; Moya-Pérez, Ángela; Agostoni, Carlo

    2015-01-01

    The gut microbiota structure, dynamics, and function result from interactions with environmental and host factors, which jointly influence the communication between the gut and peripheral tissues, thereby contributing to health programming and disease risk. Incidence of both type-1 and type-2 diabetes has increased during the past decades, suggesting that there have been changes in the interactions between predisposing genetic and environmental factors. Animal studies show that gut microbiota and its genome (microbiome) influence alterations in energy balance (increased energy harvest) and immunity (inflammation and autoimmunity), leading to metabolic dysfunction (e.g., insulin resistance and deficiency). Thus, although they have different origins, both disorders are linked by the association of the gut microbiota with the immune-metabolic axis. Human studies have also revealed shifts in microbiome signatures in diseased subjects as compared with controls, and a few of them precede the development of these disorders. These studies contribute to pinpointing specific microbiome components and functions (e.g., butyrate-producing bacteria) that can protect against both disorders. These could exert protective roles by strengthening gut barrier function and regulating inflammation, as alterations in these are a pathophysiological feature of both disorders, constituting common targets for future preventive approaches.

  2. RNA metabolism in the pathogenesis of Parkinson׳s disease.

    Science.gov (United States)

    Lu, Bingwei; Gehrke, Stephan; Wu, Zhihao

    2014-10-10

    Neurodegenerative diseases such as Parkinson׳s disease are progressive disorders of the nervous system that affect the function and maintenance of specific neuronal populations. While most disease cases are sporadic with no known cause, a small percentage of disease cases are caused by inherited genetic mutations. The identification of genes associated with the familial forms of the diseases and subsequent studies of proteins encoded by the disease genes in cellular or animal models have offered much-needed insights into the molecular and cellular mechanisms underlying disease pathogenesis. Recent studies of the familial Parkinson׳s disease genes have emphasized the importance of RNA metabolism, particularly mRNA translation, in the disease process. It is anticipated that continued studies on the role of RNA metabolism in Parkinson׳s disease will offer unifying mechanisms for understanding the cause of neuronal dysfunction and degeneration and facilitate the development of novel and rational strategies for treating this debilitating disease.

  3. Metabolic diseases and pro- and prebiotics: Mechanistic insights

    Directory of Open Access Journals (Sweden)

    Nakamura Yukiko K

    2012-06-01

    Full Text Available Abstract Metabolic diseases, such as obesity and type 2 diabetes, are world-wide health problems. The prevalence of metabolic diseases is associated with dynamic changes in dietary macronutrient intake during the past decades. Based on national statistics and from a public health viewpoint, traditional approaches, such as diet and physical activity, have been unsuccessful in decreasing the prevalence of metabolic diseases. Since the approaches strongly rely on individual’s behavior and motivation, novel science-based strategies should be considered for prevention and therapy for the diseases. Metabolism and immune system are linked. Both overnutrition and infection result in inflammation through nutrient and pathogen sensing systems which recognize compounds with structural similarities. Dietary macronutrients (fats and sugars can induce inflammation through activation of an innate immune receptor, Toll-like receptor 4 (TLR4. Long-term intake of diets high in fats and meats appear to induce chronic systemic low-grade inflammation, endotoxicity, and metabolic diseases. Recent investigations support the idea of the involvement of intestinal bacteria in host metabolism and preventative and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases. Specific intestinal bacteria seem to serve as lipopolysaccharide (LPS sources through LPS and/or bacterial translocation into the circulation due to a vulnerable microbial barrier and increased intestinal permeability and to play a role in systemic inflammation and progression of metabolic diseases. This review focuses on mechanistic links between metabolic diseases (mainly obesity and type 2 diabetes, chronic systemic low-grade inflammation, intestinal environment, and nutrition and prospective views of probiotic and prebiotic interventions for the diseases.

  4. Metabolic diseases and pro- and prebiotics: Mechanistic insights.

    Science.gov (United States)

    Nakamura, Yukiko K; Omaye, Stanley T

    2012-06-19

    Metabolic diseases, such as obesity and type 2 diabetes, are world-wide health problems. The prevalence of metabolic diseases is associated with dynamic changes in dietary macronutrient intake during the past decades. Based on national statistics and from a public health viewpoint, traditional approaches, such as diet and physical activity, have been unsuccessful in decreasing the prevalence of metabolic diseases. Since the approaches strongly rely on individual's behavior and motivation, novel science-based strategies should be considered for prevention and therapy for the diseases. Metabolism and immune system are linked. Both overnutrition and infection result in inflammation through nutrient and pathogen sensing systems which recognize compounds with structural similarities. Dietary macronutrients (fats and sugars) can induce inflammation through activation of an innate immune receptor, Toll-like receptor 4 (TLR4). Long-term intake of diets high in fats and meats appear to induce chronic systemic low-grade inflammation, endotoxicity, and metabolic diseases. Recent investigations support the idea of the involvement of intestinal bacteria in host metabolism and preventative and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases. Specific intestinal bacteria seem to serve as lipopolysaccharide (LPS) sources through LPS and/or bacterial translocation into the circulation due to a vulnerable microbial barrier and increased intestinal permeability and to play a role in systemic inflammation and progression of metabolic diseases. This review focuses on mechanistic links between metabolic diseases (mainly obesity and type 2 diabetes), chronic systemic low-grade inflammation, intestinal environment, and nutrition and prospective views of probiotic and prebiotic interventions for the diseases.

  5. Impact of the gut microbiota on inflammation, obesity, and metabolic disease.

    Science.gov (United States)

    Boulangé, Claire L; Neves, Ana Luisa; Chilloux, Julien; Nicholson, Jeremy K; Dumas, Marc-Emmanuel

    2016-04-20

    The human gut harbors more than 100 trillion microbial cells, which have an essential role in human metabolic regulation via their symbiotic interactions with the host. Altered gut microbial ecosystems have been associated with increased metabolic and immune disorders in animals and humans. Molecular interactions linking the gut microbiota with host energy metabolism, lipid accumulation, and immunity have also been identified. However, the exact mechanisms that link specific variations in the composition of the gut microbiota with the development of obesity and metabolic diseases in humans remain obscure owing to the complex etiology of these pathologies. In this review, we discuss current knowledge about the mechanistic interactions between the gut microbiota, host energy metabolism, and the host immune system in the context of obesity and metabolic disease, with a focus on the importance of the axis that links gut microbes and host metabolic inflammation. Finally, we discuss therapeutic approaches aimed at reshaping the gut microbial ecosystem to regulate obesity and related pathologies, as well as the challenges that remain in this area.

  6. Reconstruction and Analysis of Human Kidney-Specific Metabolic Network Based on Omics Data

    Directory of Open Access Journals (Sweden)

    Ai-Di Zhang

    2013-01-01

    Full Text Available With the advent of the high-throughput data production, recent studies of tissue-specific metabolic networks have largely advanced our understanding of the metabolic basis of various physiological and pathological processes. However, for kidney, which plays an essential role in the body, the available kidney-specific model remains incomplete. This paper reports the reconstruction and characterization of the human kidney metabolic network based on transcriptome and proteome data. In silico simulations revealed that house-keeping genes were more essential than kidney-specific genes in maintaining kidney metabolism. Importantly, a total of 267 potential metabolic biomarkers for kidney-related diseases were successfully explored using this model. Furthermore, we found that the discrepancies in metabolic processes of different tissues are directly corresponding to tissue's functions. Finally, the phenotypes of the differentially expressed genes in diabetic kidney disease were characterized, suggesting that these genes may affect disease development through altering kidney metabolism. Thus, the human kidney-specific model constructed in this study may provide valuable information for the metabolism of kidney and offer excellent insights into complex kidney diseases.

  7. Regulation of Metabolic Signaling in Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Albers, Peter Hjorth

    Regulation of glucose metabolism, despite intense research through decades, is still not clear. Skeletal muscle is highly important for maintaining glucose homeostasis. Regulation of skeletal muscle glucose metabolism is influenced by protein signaling and changes in the activity of metabolic enz...... interval exercise). The abundance of signaling proteins and metabolic enzymes are in most cases different in type I and type II muscle fibers, indicating that their glucose metabolism is different.......Regulation of glucose metabolism, despite intense research through decades, is still not clear. Skeletal muscle is highly important for maintaining glucose homeostasis. Regulation of skeletal muscle glucose metabolism is influenced by protein signaling and changes in the activity of metabolic...... enzymes. Skeletal muscle consists of thousands of muscle fibers. These fibers can roughly be classified into type I and type II muscle fibers. The overall aim of this PhD thesis was to investigate the effect of insulin and exercise on human muscle fiber type specific metabolic signaling. The importance...

  8. Viral diseases and human evolution

    OpenAIRE

    2000-01-01

    The interaction of man with viral agents was possibly a key factor shaping human evolution, culture and civilization from its outset. Evidence of the effect of disease, since the early stages of human speciation, through pre-historical times to the present suggest that the types of viruses associated with man changed in time. As human populations progressed technologically, they grew in numbers and density. As a consequence different viruses found suitable conditions to thrive and establish l...

  9. Functional Metabolic Map of Faecalibacterium prausnitzii, a Beneficial Human Gut Microbe

    NARCIS (Netherlands)

    Heinken, Almut; Khan, M. Tanweer; Paglia, Giuseppe; Rodionov, Dmitry A.; Harmsen, Hermie J. M.; Thiele, Ines

    2014-01-01

    The human gut microbiota plays a central role in human well-being and disease. In this study, we present an integrated, iterative approach of computational modeling, in vitro experiments, metabolomics, and genomic analysis to accelerate the identification of metabolic capabilities for poorly charact

  10. Viral diseases and human evolution

    Directory of Open Access Journals (Sweden)

    Leal Élcio de Souza

    2000-01-01

    Full Text Available The interaction of man with viral agents was possibly a key factor shaping human evolution, culture and civilization from its outset. Evidence of the effect of disease, since the early stages of human speciation, through pre-historical times to the present suggest that the types of viruses associated with man changed in time. As human populations progressed technologically, they grew in numbers and density. As a consequence different viruses found suitable conditions to thrive and establish long-lasting associations with man. Although not all viral agents cause disease and some may in fact be considered beneficial, the present situation of overpopulation, poverty and ecological inbalance may have devastating effets on human progress. Recently emerged diseases causing massive pandemics (eg., HIV-1 and HCV, dengue, etc. are becoming formidable challenges, which may have a direct impact on the fate of our species.

  11. Validation of Parkinsonian Disease-Related Metabolic Brain Patterns

    NARCIS (Netherlands)

    Teune, Laura K.; Renken, Remco J.; Mudali, Deborah; De Jong, Bauke M.; Dierckx, Rudi A.; Roerdink, Jos B.T.M.; Leenders, Klaus L.

    2013-01-01

    Background: The objective of this study was to validate disease-related metabolic brain patterns for Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Methods: The study included 20 patients with Parkinson’s disease, 21 with multiple system atrophy, and 17 with progre

  12. Report: Human biochemical genetics: an insight into inborn errors of metabolism

    Institute of Scientific and Technical Information of China (English)

    YU Chunli; SCOTT C. Ronald

    2006-01-01

    Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect intermediary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited disorder, systematically summarizing the disease phenotype and natural history, providing diagnostic rationale and methodology and treatment strategy comprise the context of human biochemical genetics. This session focused on: (1) manifestations of representative metabolic disorders; (2) the emergent technology and application of newborn screening of metabolic disorders using tandem mass spectrometry; (3) principles of managing IEM; (4) the concept of carrier testing aiming prevention. Early detection of patients with IEM allows early intervention and more options for treatment.

  13. Glucose metabolism in small subcortical structures in Parkinson's disease

    DEFF Research Database (Denmark)

    Borghammer, Per; Hansen, Søren B; Eggers, Carsten;

    2012-01-01

    Evidence from experimental animal models of Parkinson's disease (PD) suggests a characteristic pattern of metabolic perturbation in discrete, very small basal ganglia structures. These structures are generally too small to allow valid investigation by conventional positron emission tomography (PET...

  14. Magnetic resonance spectroscopy to study hepatic metabolism in diffuse liver diseases, diabetes and cancer

    Institute of Scientific and Technical Information of China (English)

    Pieter; C; Dagnelie; Susanne; Leij-Halfwerk

    2010-01-01

    This review provides an overview of the current state of the art of magnetic resonance spectroscopy (MRS) in in vivo investigations of diffuse liver disease. So far, MRS of the human liver in vivo has mainly been used as a research tool rather than a clinical tool. The liver is particularly suitable for static and dynamic metabolic studies due to its high metabolic activity. Furthermore, its relatively superfi cial position allows excellent MRS localization, while its large volume allows detection of signal...

  15. Linking Microbiota to Human Diseases: A Systems Biology Perspective.

    Science.gov (United States)

    Wu, Hao; Tremaroli, Valentina; Bäckhed, Fredrik

    2015-12-01

    The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2 diabetes (T2D), and irritable bowel syndrome, and some animal experiments have suggested causality. However, few studies have validated causality in humans and the underlying mechanisms remain largely to be elucidated. We discuss how systems biology approaches combined with new experimental technologies may disentangle some of the mechanistic details in the complex interactions of diet, microbiota, and host metabolism and may provide testable hypotheses for advancing our current understanding of human-microbiota interaction.

  16. A global evolutionary and metabolic analysis of human obesity gene risk variants.

    Science.gov (United States)

    Castillo, Joseph J; Hazlett, Zachary S; Orlando, Robert A; Garver, William S

    2017-09-05

    It is generally accepted that the selection of gene variants during human evolution optimized energy metabolism that now interacts with our obesogenic environment to increase the prevalence of obesity. The purpose of this study was to perform a global evolutionary and metabolic analysis of human obesity gene risk variants (110 human obesity genes with 127 nearest gene risk variants) identified using genome-wide association studies (GWAS) to enhance our knowledge of early and late genotypes. As a result of determining the mean frequency of these obesity gene risk variants in 13 available populations from around the world our results provide evidence for the early selection of ancestral risk variants (defined as selection before migration from Africa) and late selection of derived risk variants (defined as selection after migration from Africa). Our results also provide novel information for association of these obesity genes or encoded proteins with diverse metabolic pathways and other human diseases. The overall results indicate a significant differential evolutionary pattern for the selection of obesity gene ancestral and derived risk variants proposed to optimize energy metabolism in varying global environments and complex association with metabolic pathways and other human diseases. These results are consistent with obesity genes that encode proteins possessing a fundamental role in maintaining energy metabolism and survival during the course of human evolution. Copyright © 2017. Published by Elsevier B.V.

  17. Reconstruction of genome-scale metabolic models for 126 human tissues using mCADRE.

    Science.gov (United States)

    Wang, Yuliang; Eddy, James A; Price, Nathan D

    2012-12-13

    Human tissues perform diverse metabolic functions. Mapping out these tissue-specific functions in genome-scale models will advance our understanding of the metabolic basis of various physiological and pathological processes. The global knowledgebase of metabolic functions categorized for the human genome (Human Recon 1) coupled with abundant high-throughput data now makes possible the reconstruction of tissue-specific metabolic models. However, the number of available tissue-specific models remains incomplete compared with the large diversity of human tissues. We developed a method called metabolic Context-specificity Assessed by Deterministic Reaction Evaluation (mCADRE). mCADRE is able to infer a tissue-specific network based on gene expression data and metabolic network topology, along with evaluation of functional capabilities during model building. mCADRE produces models with similar or better functionality and achieves dramatic computational speed up over existing methods. Using our method, we reconstructed draft genome-scale metabolic models for 126 human tissue and cell types. Among these, there are models for 26 tumor tissues along with their normal counterparts, and 30 different brain tissues. We performed pathway-level analyses of this large collection of tissue-specific models and identified the eicosanoid metabolic pathway, especially reactions catalyzing the production of leukotrienes from arachidnoic acid, as potential drug targets that selectively affect tumor tissues. This large collection of 126 genome-scale draft metabolic models provides a useful resource for studying the metabolic basis for a variety of human diseases across many tissues. The functionality of the resulting models and the fast computational speed of the mCADRE algorithm make it a useful tool to build and update tissue-specific metabolic models.

  18. Evolution of Microbial Quorum Sensing to Human Global Quorum Sensing: An Insight into How Gap Junctional Intercellular Communication Might Be Linked to the Global Metabolic Disease Crisis

    Directory of Open Access Journals (Sweden)

    James E. Trosko

    2016-06-01

    Full Text Available The first anaerobic organism extracted energy for survival and reproduction from its source of nutrients, with the genetic means to ensure protection of its individual genome but also its species survival. While it had a means to communicate with its community via simple secreted molecules (“quorum sensing”, the eventual shift to an aerobic environment led to multi-cellular metazoan organisms, with evolutionary-selected genes to form extracellular matrices, stem cells, stem cell niches, and a family of gap junction or “connexin” genes. These germinal and somatic stem cells responded to extracellular signals that triggered intra-cellular signaling to regulate specific genes out of the total genome. These extra-cellular induced intra-cellular signals also modulated gap junctional intercellular communication (GJIC in order to regulate the new cellular functions of symmetrical and asymmetrical cell division, cell differentiation, modes of cell death, and senescence. Within the hierarchical and cybernetic concepts, differentiated by neurons organized in the brain of the Homo sapiens, the conscious mind led to language, abstract ideas, technology, myth-making, scientific reasoning, and moral decision–making, i.e., the creation of culture. Over thousands of years, this has created the current collision between biological and cultural evolution, leading to the global “metabolic disease” crisis.

  19. Evolution of Microbial Quorum Sensing to Human Global Quorum Sensing: An Insight into How Gap Junctional Intercellular Communication Might Be Linked to the Global Metabolic Disease Crisis

    Science.gov (United States)

    Trosko, James E.

    2016-01-01

    The first anaerobic organism extracted energy for survival and reproduction from its source of nutrients, with the genetic means to ensure protection of its individual genome but also its species survival. While it had a means to communicate with its community via simple secreted molecules (“quorum sensing”), the eventual shift to an aerobic environment led to multi-cellular metazoan organisms, with evolutionary-selected genes to form extracellular matrices, stem cells, stem cell niches, and a family of gap junction or “connexin” genes. These germinal and somatic stem cells responded to extracellular signals that triggered intra-cellular signaling to regulate specific genes out of the total genome. These extra-cellular induced intra-cellular signals also modulated gap junctional intercellular communication (GJIC) in order to regulate the new cellular functions of symmetrical and asymmetrical cell division, cell differentiation, modes of cell death, and senescence. Within the hierarchical and cybernetic concepts, differentiated by neurons organized in the brain of the Homo sapiens, the conscious mind led to language, abstract ideas, technology, myth-making, scientific reasoning, and moral decision–making, i.e., the creation of culture. Over thousands of years, this has created the current collision between biological and cultural evolution, leading to the global “metabolic disease” crisis. PMID:27314399

  20. The emerging role of the intestine in metabolic diseases.

    Science.gov (United States)

    Bradley, William D; Zwingelstein, Catherine; Rondinone, Cristina M

    2011-07-01

    The intestine is an important metabolic organ that has gained attention in recent years for the newly identified role that it plays in the pathophysiology of various metabolic diseases including obesity, insulin resistance and diabetes. Recent insights regarding the role of enteroendocrine hormones, such as GIP, GLP-1, and PYY in metabolic diseases, as well as the emerging role of the gut microbial community and gastric bypass bariatric surgeries in modulating metabolic function and dysfunction have sparked a wave of interest in understanding the mechanisms involved, in an effort to identify new therapeutics and novel regulators of metabolism. This review summarizes the current evidence that the gastrointestinal tract has a key role in the development of obesity, inflammation, insulin resistance and diabetes and discusses the possible players that can be targeted for therapeutic intervention.

  1. Metabolic Modulators in Heart Disease: Past, Present, and Future.

    Science.gov (United States)

    Lopaschuk, Gary D

    2017-07-01

    Ischemic heart disease and heart failure are leading causes of mortality and morbidity worldwide. They continue to be major burden on health care systems throughout the world, despite major advances made over the past 40 years in developing new therapeutic approaches to treat these debilitating diseases. A potential therapeutic approach that has been underutilized in treating ischemic heart disease and heart failure is "metabolic modulation." Major alterations in myocardial energy substrate metabolism occur in ischemic heart disease and heart failure, and are associated with an energy deficit in the heart. A metabolic shift from mitochondrial oxidative metabolism to glycolysis, as well as an uncoupling between glycolysis and glucose oxidation, plays a crucial role in the development of cardiac inefficiency (oxygen consumed per work performed) and functional impairment in ischemic heart disease as well as in heart failure. This has led to the concept that optimizing energy substrate use with metabolic modulators can be a potentially promising approach to decrease the severity of ischemic heart disease and heart failure, primarily by improving cardiac efficiency. Two approaches for metabolic modulator therapy are to stimulate myocardial glucose oxidation and/or inhibit fatty acid oxidation. In this review, the past, present, and future of metabolic modulators as an approach to optimizing myocardial energy substrate metabolism and treating ischemic heart disease and heart failure are discussed. This includes a discussion of pharmacological interventions that target enzymes involved in fatty acid uptake, fatty acid oxidation, and glucose oxidation in the heart, as well as enzymes involved in ketone and branched chain amino acid catabolism in the heart. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  2. Electromagnetic respiratory effort harvester: human testing and metabolic cost analysis.

    Science.gov (United States)

    Shahhaidar, E; Padasdao, B; Romine, R; Stickley, C; Lubecke, O Boric

    2015-03-01

    Remote health monitoring is increasingly recognized as a valuable tool in chronic disease management. Continuous respiratory monitoring could be a powerful tool in managing chronic diseases, however it is infrequently performed because of obtrusiveness and inconvenience of the existing methods. The movements of the chest wall and abdominal area during normal breathing can be monitored and harvested to enable self-powered wearable biosensors for continuous remote monitoring. This paper presents human testing results of a light-weight (30 g), wearable respiratory effort energy harvesting sensor. The harvester output voltage, power, and its metabolic burden, are measured on twenty subjects in two resting and exercise conditions each lasting 5 min. The system includes two off-the-shelf miniature electromagnetic generators harvesting and sensing thoracic and abdominal movements. Modules can be placed in series to increase the output voltage for rectification purposes. Electromagnetic respiratory effort harvester/sensor system can produce up to 1.4 V, 6.44 mW, and harvests 30.4 mJ during a 5-min exercise stage. A statistical paired t-test analysis of the calculated EE confirmed there is no significant change ( P > 0.05 ) in the metabolic rate of subjects wearing the electromagnetic harvester and biosensor.

  3. Predictive association of copper metabolism proteins with Alzheimer's disease and Parkinson's disease: a preliminary perspective.

    Science.gov (United States)

    Pal, Amit; Kumar, Ashok; Prasad, Rajendra

    2014-02-01

    Neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD), constitute a major worldwide health problem. Several hypothesis have been put forth to elucidate the basis of onset and pathogenesis of AD and PD; however, till date, none of these seems to clearly elucidate the complex pathoetiology of these disorders. Notably, copper dyshomeostasis has been shown to underlie the pathophysiology of several neurodegenerative diseases including AD and PD. Numerous studies have concluded beyond doubt that imbalance in copper homeostatic mechanisms in conjunction with aging causes an acceleration in the copper toxicity elicited oxidative stress, which is detrimental to the central nervous system. Amyloid precursor protein and α-synuclein protein involved in AD and PD are copper binding proteins, respectively. In this review, we have discussed the possible association of copper metabolism proteins with AD and PD along with briefly outlining the expanding proportion of "copper interactome" in human biology. Using network biology, we found that copper metabolism proteins, superoxide dismutase 1 and ceruloplasmin may represent direct and indirect link with AD and PD, respectively.

  4. The metabolic syndrome and vascular disease

    NARCIS (Netherlands)

    Olijhoek, Jobien Karen

    2006-01-01

    In the Western population cardiovascular diseases are the most common cause of mortality and morbidity. There are several important risk factors for cardiovascular diseases, among them hypertension, hypercholesterolemia, diabetes and obesity. The clustering of cardiovascular risk factors associated

  5. The metabolic syndrome and vascular disease

    NARCIS (Netherlands)

    Olijhoek, Jobien Karen

    2006-01-01

    In the Western population cardiovascular diseases are the most common cause of mortality and morbidity. There are several important risk factors for cardiovascular diseases, among them hypertension, hypercholesterolemia, diabetes and obesity. The clustering of cardiovascular risk factors associated

  6. Cardiac rehabilitation programs improve metabolic parameters in patients with the metabolic syndrome and coronary heart disease.

    Science.gov (United States)

    Pérez, Ignacio P; Zapata, Maria A; Cervantes, Carlos E; Jarabo, Rosario M; Grande, Cristina; Plaza, Rose; Garcia, Sara; Rodriguez, Miriam L; Crespo, Silvia; Perea, Jesús

    2010-05-01

    This study was performed to determine the effectiveness of a cardiac rehabilitation and exercise training program on metabolic parameters and coronary risk factors in patients with the metabolic syndrome and coronary heart disease. The study involved 642 patients with coronary heart disease. Of them, 171 (26.7%) fulfilled criteria for the metabolic syndrome. Clinical data, laboratory tests, and exercise testing were performed before and after the program, which lasted 2 to 3 months. Except for waist circumference, there were no significant differences between groups; blood pressure, high-density lipoprotein cholesterol, triglycerides, and fasting glucose improvements during the follow-up were higher in patients with the metabolic syndrome (all Pmetabolic syndrome, functional capacity increased by 26.45% ( Pmetabolic equivalents, with a slight increase of 1.25% ( P=not significant) in the double product. Patients with the metabolic syndrome who took part in this secondary prevention program reported improvements in cardiovascular risk profile and functional capacity.

  7. Chromatin remodeling and human disease.

    Science.gov (United States)

    Huang, Cheng; Sloan, Emily A; Boerkoel, Cornelius F

    2003-06-01

    In the past few years, there has been a nascent convergence of scientific understanding of inherited human diseases with epigenetics. Identified epigenetic processes involved in human disease include covalent DNA modifications, covalent histone modifications, and histone relocation. Each of these processes influences chromatin structure and thereby regulates gene expression and DNA methylation, replication, recombination, and repair. The importance of these processes for nearly all aspects of normal growth and development is illustrated by the array of multi-system disorders and neoplasias caused by their dysregulation.

  8. Bile Acid Signaling in Liver Metabolism and Diseases

    Directory of Open Access Journals (Sweden)

    Tiangang Li

    2012-01-01

    Full Text Available Obesity, diabetes, and metabolic syndromes are increasingly recognized as health concerns worldwide. Overnutrition and insulin resistance are the major causes of diabetic hyperglycemia and hyperlipidemia in humans. Studies in the past decade provide evidence that bile acids are not just biological detergents facilitating gut nutrient absorption, but also important metabolic regulators of glucose and lipid homeostasis. Pharmacological alteration of bile acid metabolism or bile acid signaling pathways such as using bile acid receptor agonists or bile acid binding resins may be a promising therapeutic strategy for the treatment of obesity and diabetes. On the other hand, bile acid signaling is complex, and the molecular mechanisms mediating the bile acid effects are still not completely understood. This paper will summarize recent advances in our understanding of bile acid signaling in regulation of glucose and lipid metabolism, and the potentials of developing novel therapeutic strategies that target bile acid metabolism for the treatment of metabolic disorders.

  9. Exercise-induced myokines in health and metabolic diseases

    Directory of Open Access Journals (Sweden)

    Byunghun So

    2014-12-01

    Full Text Available Skeletal muscle has been emerging as a research field since the past 2 decades. Contraction of a muscle, which acts as a secretory organ, stimulates production, secretion, and expression of cytokines or other muscle fiber-derived peptides, i.e., myokines. Exercise-induced myokines influence crosstalk between different organs in an autocrine, endocrine, or paracrine fashion. Myokines are recently recognized as potential candidates for treating metabolic diseases through their ability to stimulate AMP-activated protein kinase signaling, increase glucose uptake, and improve lipolysis. Myokines may have positive effects on metabolic disorders, type 2 diabetes, or obesity. Numerous studies on myokines suggested that myokines offer a potential treatment option for preventing metabolic diseases. This review summarizes the current understanding of the positive effects of exercise-induced myokines, such as interleukin-15, brain-derived neurotrophic factor, leukemia inhibitory factor, irisin, fibroblast growth factor 21, and secreted protein acidic and rich in cysteine, on metabolic diseases.

  10. Obesity-related metabolic dysfunction in dogs: a comparison with human metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Tvarijonaviciute Asta

    2012-08-01

    Full Text Available Abstract Background Recently, metabolic syndrome (MS has gained attention in human metabolic medicine given its associations with development of type 2 diabetes mellitus and cardiovascular disease. Canine obesity is associated with the development of insulin resistance, dyslipidaemia, and mild hypertension, but the authors are not aware of any existing studies examining the existence or prevalence of MS in obese dogs. Thirty-five obese dogs were assessed before and after weight loss (median percentage loss 29%, range 10-44%. The diagnostic criteria of the International Diabetes Federation were modified in order to define canine obesity-related metabolic dysfunction (ORMD, which included a measure of adiposity (using a 9-point body condition score [BCS], systolic blood pressure, fasting plasma cholesterol, plasma triglyceride, and fasting plasma glucose. By way of comparison, total body fat mass was measured by dual-energy X-ray absorptiometry, whilst total adiponectin, fasting insulin, and high-sensitivity C-reactive protein (hsCRP were measured using validated assays. Results Systolic blood pressure (P = 0.008, cholesterol (P = 0.003, triglyceride (P = 0.018, and fasting insulin (P P = 0.001. However, hsCRP did not change with weight loss. Prior to weight loss, 7 dogs were defined as having ORMD, and there was no difference in total fat mass between these dogs and those who did not meet the criteria for ORMD. However, plasma adiponectin concentration was less (P = 0.031, and plasma insulin concentration was greater (P = 0.030 in ORMD dogs. Conclusions In this study, approximately 20% of obese dogs suffer from ORMD, and this is characterized by hypoadiponectinaemia and hyperinsulinaemia. These studies can form the basis of further investigations to determine path genetic mechanisms and the health significance for dogs, in terms of disease associations and outcomes of weight loss.

  11. Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health.

    Science.gov (United States)

    O'Brien, Peter J; Siraki, Arno G; Shangari, Nandita

    2005-08-01

    Aldehydes are organic compounds that are widespread in nature. They can be formed endogenously by lipid peroxidation (LPO), carbohydrate or metabolism ascorbate autoxidation, amine oxidases, cytochrome P-450s, or myeloperoxidase-catalyzed metabolic activation. This review compares the reactivity of many aldehydes towards biomolecules particularly macromolecules. Furthermore, it includes not only aldehydes of environmental or occupational concerns but also dietary aldehydes and aldehydes formed endogenously by intermediary metabolism. Drugs that are aldehydes or form reactive aldehyde metabolites that cause side-effect toxicity are also included. The effects of these aldehydes on biological function, their contribution to human diseases, and the role of nucleic acid and protein carbonylation/oxidation in mutagenicity and cytotoxicity mechanisms, respectively, as well as carbonyl signal transduction and gene expression, are reviewed. Aldehyde metabolic activation and detoxication by metabolizing enzymes are also reviewed, as well as the toxicological and anticancer therapeutic effects of metabolizing enzyme inhibitors. The human health risks from clinical and animal research studies are reviewed, including aldehydes as haptens in allergenic hypersensitivity diseases, respiratory allergies, and idiosyncratic drug toxicity; the potential carcinogenic risks of the carbonyl body burden; and the toxic effects of aldehydes in liver disease, embryo toxicity/teratogenicity, diabetes/hypertension, sclerosing peritonitis, cerebral ischemia/neurodegenerative diseases, and other aging-associated diseases.

  12. Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders.

    Science.gov (United States)

    Cai, Huan; Cong, Wei-na; Ji, Sunggoan; Rothman, Sarah; Maudsley, Stuart; Martin, Bronwen

    2012-01-01

    Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.

  13. Magnesium and metabolic syndrome: The role of magnesium in health and disease

    Science.gov (United States)

    Metabolic syndrome is a constellation of conditions associated with elevated risk of diabetes and cardiovascular disease. Magnesium, the fourth most abundant cation in the human body and required in over 300 enzymatic reactions, has been shown in experimental, observational, and clinical studies to ...

  14. Going nuclear in metabolic and cardiovascular disease

    OpenAIRE

    Glass, Christopher K.

    2006-01-01

    Estrogen receptors, PPARs, and liver X receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors that regulate diverse aspects of development and homeostasis. Recent studies of the biologic roles of these receptors and their mechanisms of action have significantly advanced our understanding of transcriptional programs that control lipid and carbohydrate metabolism, immunity and inflammation, and wound repair. These findings provide insights into the t...

  15. Retinal Remodeling And Metabolic Alterations in Human AMD

    Directory of Open Access Journals (Sweden)

    Bryan William Jones

    2016-04-01

    Full Text Available Age-related macular degeneration (AMD is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression.The pathways and mechanisms through which genetic and non-genetic risk factors modulate development of AMD pathogenesis remain largely unexplored. Moreover, current treatment for AMD is palliative and limited to wet/exudative forms. Retina is a complex, heterocellular tissue and most retinal cell classes are impacted or altered in AMD. Defining disease and stage-specific cytoarchitectural and metabolic responses in AMD is critical for highlighting targets for intervention. The goal of this paper is to illustrate cell types impacted in AMD and demonstrate the implications of those changes, likely beginning in the retinal pigment epithelium (RPE, for remodeling of the the neural retina.Tracking heterocellular responses in disease progression is best achieved with computational molecular phenotyping (CMP, a tool that enables acquisition of a small molecule fingerprint for every cell in the retina. CMP uncovered critical cellular and molecular pathologies (remodeling and reprogramming in progressive retinal degenerations such as retinitis pigmentosa (RP. We now applied these approaches to normal human and AMD tissues mapping progression of cellular and molecular changes in AMD retinas, including late-stage forms of the disease.Major findings: 1 Evidence of metabolic instability in RPE in dry-AMD.2 Photoreceptors show clear indications of stress prior to cell death.3 Cone opsin processing by the RPE in AMD retinas may be differentially compromised vs. rod opsin.4 Müller cells in AMD exhibit

  16. Typical Cerebral Metabolic Patterns in Neurodegenerative Brain Diseases

    NARCIS (Netherlands)

    Teune, Laura K.; Bartels, Anna L.; de Jong, Bauke M.; Willemsen, Antoon T. M.; Eshuis, Silvia A.; de Vries, Jeroen J.; van Oostrom, Joost C. H.; Leenders, Klaus L.

    2010-01-01

    The differential diagnosis of neurodegenerative brain diseases on clinical grounds is difficult, especially at an early disease stage. Several studies have found specific regional differences of brain metabolism applying [F-18]-fluoro-deoxyglucose positron emission tomography (FDG-PET), suggesting t

  17. GPR120 agonism as a countermeasure against metabolic diseases.

    Science.gov (United States)

    Cornall, Lauren M; Mathai, Michael L; Hryciw, Deanne H; McAinch, Andrew J

    2014-05-01

    Obesity, type 2 diabetes mellitus and cardiovascular disease are at epidemic proportions in developed nations globally, representing major causes of ill-health and premature death. The search for drug targets to counter the growing prevalence of metabolic diseases has uncovered G-protein-coupled receptor 120 (GPR120). GPR120 agonism has been shown to improve inflammation and metabolic health on a systemic level via regulation of adiposity, gastrointestinal peptide secretion, taste preference and glucose homeostasis. Therefore, GPR120 agonists present as a novel therapeutic option that could be exploited for the treatment of impaired metabolic health. This review summarizes the current knowledge of GPR120 functionality and the potential applications of GPR120-specific agonists for the treatment of disease states such as obesity, type 2 diabetes mellitus and cardiovascular disease.

  18. Metabolic biomarkers and gallstone disease - a population-based study

    DEFF Research Database (Denmark)

    Shabanzadeh, Daniel Mønsted; Skaaby, Tea; Sørensen, Lars Tue

    2017-01-01

    OBJECTIVES: The objectives for this study were to examine the associations between metabolic biomarkers of obesity including insulin resistance, vascular dysfunction, systemic inflammation, genetic susceptibility and ultrasound proven gallstone disease or cholecystectomy in a population-based cross......). RESULTS: Gallstone disease was associated with fasting glucose (OR 1.14, 95% CI [1.05;1.24]), fasting insulin (OR 1.03, 95% CI [1.01;1.05]), homeostasis model assessment insulin resistance (OR 1.18, 95% CI [1.02;1.36]), the metabolic syndrome (OR 1.51, 95% CI [1.16;1.96]), white blood cell count (OR 1......-sectional study. MATERIAL AND METHODS: A total of 2650 participants were included, of whom 422 had gallstone disease. Associations between selected metabolic biomarkers and gallstone disease were estimated by multivariable logistic regression models and expressed as odds ratio (OR) and 95% confidence interval (CI...

  19. The role of gut microbiota in human metabolism

    NARCIS (Netherlands)

    Vrieze, A.

    2013-01-01

    This thesis supports the hypothesis that gut microbiota can be viewed as an ‘exteriorised organ’ that contributes to energy metabolism and the modulation of our immune system. Following Koch’s postulates, it has now been shown that gut microbiota are associated with metabolic disease and that these

  20. The role of gut microbiota in human metabolism

    NARCIS (Netherlands)

    Vrieze, A.

    2013-01-01

    This thesis supports the hypothesis that gut microbiota can be viewed as an ‘exteriorised organ’ that contributes to energy metabolism and the modulation of our immune system. Following Koch’s postulates, it has now been shown that gut microbiota are associated with metabolic disease and that these

  1. The link between iron, metabolic syndrome, and Alzheimer's disease.

    Science.gov (United States)

    Grünblatt, Edna; Bartl, Jasmin; Riederer, Peter

    2011-03-01

    Both Alzheimer's disease (AD), the most common form of dementia, and type-2 diabetes mellitus (T2DM), a disease associated with metabolic syndrome (MetS), affect a great number of the world population and both have increased prevalence with age. Recently, many studies demonstrated that pre-diabetes, MetS, and T2DM are risk factors in the development of AD and have many common mechanisms. The main focus of studies is the insulin resistance outcome found both in MetS as well as in brains of AD subjects. However, oxidative stress (OS)-related mechanisms, which are well known to be involved in AD, including mitochondrial dysfunction, elevated iron concentration, reactive oxygen species (ROS), and stress-related enzyme or proteins (e.g. heme oxygenase-1, transferrin, etc.), have not been elucidated in MetS or T2DM brains although OS and iron are involved in the degeneration of the pancreatic islet β cells. Therefore, this review sets to cover the current literature regarding OS and iron in MetS and T2DM and the similarities to mechanisms in AD both in human subjects as well as in animal models.

  2. Enzymology of mammalian NAD metabolism in health and disease.

    Science.gov (United States)

    Magni, Giulio; Orsomando, Giuseppe; Raffelli, Nadia; Ruggieri, Silverio

    2008-05-01

    Mounting evidence attests to the paramount importance of the non-redox NAD functions. Indeed, NAD homeostasis is related to the free radicals-mediated production of reactive oxygen species responsible for irreversible cellular damage in infectious disease, diabetes, inflammatory syndromes, neurodegeneration and cancer. Because the cellular redox status depends on both the absolute concentration of pyridine dinucleotides and their respective ratios of oxidized and reduced forms (i.e., NAD/NADH and NADP/NADPH), it is conceivable that an altered regulation of the synthesis and degradation of NAD impairs the cell redox state and likely contributes to the mechanisms underlying the pathogenesis of the above mentioned diseases. Taking into account the recent appearance in the literature of comprehensive reviews covering different aspects of the significance of NAD metabolism, with particular attention to the enzymes involved in NAD cleavage, this monograph includes the most recent results on NAD biosynthesis in mammals and humans. Due to recent findings on nicotinamide riboside as a nutrient, its inclusion under "niacins" is proposed. Here, the enzymes involved in the de novo and reutilization pathways are overviewed.

  3. Potential Linkage Between Cerebrovascular Diseases and Metabolic Syndrome.

    Science.gov (United States)

    Jabir, Nasimudeen R; Firoz, Chelapram Kandy; Khan, Mohd Shahnawaz; Zaidi, Syed Kashif; Ashraf, Ghulam Md; Shakil, Shazi; Kamal, Mohammad Amjad; Tabrez, Shams

    2017-01-01

    Cerebrovascular disease (CD) and metabolic syndrome (MetS) are two devastating health dilemma that continues to be a potential contributor to disability and mortality in human population all across the world. Scientific data clearly shows several mechanistic similarities between these two co-existing and interlinked conditions. The linkage exacerbates ongoing patho-physiological condition towards more lethal events. In view of the presence of modifiable risk factors in both CD and MetS, their management holds potential therapeutic value. Hence, developing common treatment strategies for these diseases could involve common molecular agents. In this communication, we have summarized some of the common pathological conditions viz. abdominal obesity, insulin resistance, dyslipidemia, hypertension, and endothelial dysfunction that further deteriorate existing homeostasis in CD and MetS. Based on our article, it is advocated that substantial improvements in novel multi-targeted drug discovery could provide the effective treatment methods in order to avoid the fatal complications related with CD and MetS. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans

    DEFF Research Database (Denmark)

    Pant, Sameer Dinkar; Karlskov-Mortensen, Peter; Jacobsen, Mette Juul

    2015-01-01

    in different populations. Several important genes previously associated to obesity in human studies, along with novel genes were identified. Altogether, this study provides novel insight that may further the current understanding of the molecular mechanisms underlying human obesity.......The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological...... features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits...

  5. Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans

    DEFF Research Database (Denmark)

    Pant, Sameer Dinkar; Karlskov-Mortensen, Peter; Jacobsen, Mette Juul;

    2015-01-01

    The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological...... features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits...... in the parental generation. Several obesity and metabolic phenotypes were recorded (n = 35) from birth to slaughter (242 ± 48 days), including body composition determined at about two months of age (63 ± 10 days) via dual-energy x-ray absorptiometry (DXA) scanning. All pigs were genotyped using Illumina Porcine...

  6. Fatigue in Parkinson's disease: The contribution of cerebral metabolic changes.

    Science.gov (United States)

    Cho, Sang Soo; Aminian, Kelly; Li, Crystal; Lang, Anthony E; Houle, Sylvain; Strafella, Antonio P

    2017-01-01

    Fatigue is a common and disabling non-motor symptom in Parkinson's disease associated with a feeling of overwhelming lack of energy. The aim of this study was to identify the neural substrates that may contribute to the development of fatigue in Parkinson's disease. Twenty-three Parkinson's disease patients meeting UK Brain Bank criteria for the diagnosis of idiopathic Parkinson's disease were recruited and completed the 2-[(18) F]fluoro-2-deoxy-D-glucose (FDG)-PET scan. The metabolic activities of Parkinson's disease patients with fatigue were compared to those without fatigue using statistical parametric mapping analysis. The Parkinson's disease group exhibiting higher level of fatigue showed anti-correlated metabolic changes in cortical regions associated with the salience (i.e., right insular region) and default (i.e., bilateral posterior cingulate cortex) networks. The metabolic abnormalities detected in these brain regions displayed a significant correlation with level of fatigue and were associated with a disruption of the functional correlations with different cortical areas. These observations suggest that fatigue in Parkinson's disease may be the expression of metabolic abnormalities and impaired functional interactions between brain regions linked to the salience network and other neural networks. Hum Brain Mapp 38:283-292, 2017. © 2016 Wiley Periodicals, Inc.

  7. Inflammation meets metabolic disease: Gut feeling mediated by GLP-1

    Directory of Open Access Journals (Sweden)

    Tamara eZietek

    2016-04-01

    Full Text Available Chronic diseases such as obesity and diabetes, cardiovascular and inflammatory bowel diseases (IBD share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways like the unfolded protein response (UPR, alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular the L cell-derived incretin hormone glucagon-like peptide 1 (GLP-1 has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D. Yet, accumulating data indicates a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment including the microbiota via receptors and transporters. Subsequently mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling.This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity and disease.

  8. Obesity, Metabolic Syndrome, and Airway Disease: A Bioenergetic Problem?

    OpenAIRE

    2014-01-01

    Common pathophysiological mechanisms are increasingly being recognized between obesity, metabolic dysfunction, and airway disease. Obesity increases asthma risk or severity, in multiple studies across the globe. Metabolic changes of obesity such as diabetes or insulin resistance are associated with asthma as well as poorer lung function. Insulin resistance has also been found to increase asthma risk independent of body mass. Conversely, asthma has been associated with abnormal glucose and lip...

  9. Metabolic Effects of the Very-Low-Carbohydrate Diets: Misunderstood "Villains" of Human Metabolism

    Directory of Open Access Journals (Sweden)

    Manninen Anssi H

    2004-12-01

    Full Text Available Abstract During very low carbohydrate intake, the regulated and controlled production of ketone bodies causes a harmless physiological state known as dietary ketosis. Ketone bodies flow from the liver to extra-hepatic tissues (e.g., brain for use as a fuel; this spares glucose metabolism via a mechanism similar to the sparing of glucose by oxidation of fatty acids as an alternative fuel. In comparison with glucose, the ketone bodies are actually a very good respiratory fuel. Indeed, there is no clear requirement for dietary carbohydrates for human adults. Interestingly, the effects of ketone body metabolism suggest that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. Also, the recent landmark study showed that a very-low-carbohydrate diet resulted in a significant reduction in fat mass and a concomitant increase in lean body mass in normal-weight men. Contrary to popular belief, insulin is not needed for glucose uptake and utilization in man. Finally, both muscle fat and carbohydrate burn in an amino acid flame.

  10. A clinical perspective of obesity, metabolic syndrome and cardiovascular disease.

    Science.gov (United States)

    Han, Thang S; Lean, Mike Ej

    2016-01-01

    The metabolic syndrome is a condition characterized by a special constellation of reversible major risk factors for cardiovascular disease and type 2 diabetes. The main, diagnostic, components are reduced HDL-cholesterol, raised triglycerides, blood pressure and fasting plasma glucose, all of which are related to weight gain, specifically intra-abdominal/ectopic fat accumulation and a large waist circumference. Using internationally adopted arbitrary cut-off values for waist circumference, having metabolic syndrome doubles the risk of cardiovascular disease, but offers an effective treatment approach through weight management. Metabolic syndrome now affects 30-40% of people by age 65, driven mainly by adult weight gain, and by a genetic or epigenetic predisposition to intra-abdominal/ectopic fat accumulation related to poor intra-uterine growth. Metabolic syndrome is also promoted by a lack of subcutaneous adipose tissue, low skeletal muscle mass and anti-retroviral drugs. Reducing weight by 5-10%, by diet and exercise, with or without, anti-obesity drugs, substantially lowers all metabolic syndrome components, and risk of type 2 diabetes and cardiovascular disease. Other cardiovascular disease risk factors such as smoking should be corrected as a priority. Anti-diabetic agents which improve insulin resistance and reduce blood pressure, lipids and weight should be preferred for diabetic patients with metabolic syndrome. Bariatric surgery offers an alternative treatment for those with BMI ≥ 40 or 35-40 kg/m(2) with other significant co-morbidity. The prevalence of the metabolic syndrome and cardiovascular disease is expected to rise along with the global obesity epidemic: greater emphasis should be given to effective early weight-management to reduce risk in pre-symptomatic individuals with large waists.

  11. A clinical perspective of obesity, metabolic syndrome and cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Thang S Han

    2016-02-01

    Full Text Available The metabolic syndrome is a condition characterized by a special constellation of reversible major risk factors for cardiovascular disease and type 2 diabetes. The main, diagnostic, components are reduced HDL-cholesterol, raised triglycerides, blood pressure and fasting plasma glucose, all of which are related to weight gain, specifically intra-abdominal/ectopic fat accumulation and a large waist circumference. Using internationally adopted arbitrary cut-off values for waist circumference, having metabolic syndrome doubles the risk of cardiovascular disease, but offers an effective treatment approach through weight management. Metabolic syndrome now affects 30–40% of people by age 65, driven mainly by adult weight gain, and by a genetic or epigenetic predisposition to intra-abdominal/ectopic fat accumulation related to poor intra-uterine growth. Metabolic syndrome is also promoted by a lack of subcutaneous adipose tissue, low skeletal muscle mass and anti-retroviral drugs. Reducing weight by 5–10%, by diet and exercise, with or without, anti-obesity drugs, substantially lowers all metabolic syndrome components, and risk of type 2 diabetes and cardiovascular disease. Other cardiovascular disease risk factors such as smoking should be corrected as a priority. Anti-diabetic agents which improve insulin resistance and reduce blood pressure, lipids and weight should be preferred for diabetic patients with metabolic syndrome. Bariatric surgery offers an alternative treatment for those with BMI ≥ 40 or 35–40 kg/m2 with other significant co-morbidity. The prevalence of the metabolic syndrome and cardiovascular disease is expected to rise along with the global obesity epidemic: greater emphasis should be given to effective early weight-management to reduce risk in pre-symptomatic individuals with large waists.

  12. Proteins aggregation and human diseases

    Science.gov (United States)

    Hu, Chin-Kun

    2015-04-01

    Many human diseases and the death of most supercentenarians are related to protein aggregation. Neurodegenerative diseases include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), frontotemporallobar degeneration, etc. Such diseases are due to progressive loss of structure or function of neurons caused by protein aggregation. For example, AD is considered to be related to aggregation of Aβ40 (peptide with 40 amino acids) and Aβ42 (peptide with 42 amino acids) and HD is considered to be related to aggregation of polyQ (polyglutamine) peptides. In this paper, we briefly review our recent discovery of key factors for protein aggregation. We used a lattice model to study the aggregation rates of proteins and found that the probability for a protein sequence to appear in the conformation of the aggregated state can be used to determine the temperature at which proteins can aggregate most quickly. We used molecular dynamics and simple models of polymer chains to study relaxation and aggregation of proteins under various conditions and found that when the bending-angle dependent and torsion-angle dependent interactions are zero or very small, then protein chains tend to aggregate at lower temperatures. All atom models were used to identify a key peptide chain for the aggregation of insulin chains and to find that two polyQ chains prefer anti-parallel conformation. It is pointed out that in many cases, protein aggregation does not result from protein mis-folding. A potential drug from Chinese medicine was found for Alzheimer's disease.

  13. Chagas disease and human migration

    Directory of Open Access Journals (Sweden)

    Felipe Guhl

    2000-08-01

    Full Text Available Human Chagas disease is a purely accidental occurrence. As humans came into contact with the natural foci of infection might then have become infected as a single addition to the already extensive host range of Trypanosoma cruzi that includes other primates. Thus began a process of adaptation and domiciliation to human habitations through which the vectors had direct access to abundant food as well as protection from climatic changes and predators. Our work deals with the extraction and specific amplification by polymerase chain reaction of T. cruzi DNA obtained from mummified human tissues and the positive diagnosis of Chagas disease in a series of 4,000-year-old Pre-Hispanic human mummies from the northern coast of Chile. The area has been inhabited at least for 7,000 years, first by hunters, fishers and gatherers, and then gradually by more permanent settlements. The studied specimens belonged to the Chinchorro culture, a people inhabiting the area now occupied by the modern city of Arica. These were essentially fishers with a complex religious ideology, which accounts for the preservation of their dead in the way of mummified bodies, further enhanced by the extremely dry conditions of the desert. Chinchorro mummies are, perhaps, the oldest preserved bodies known to date.

  14. Metabolic Syndrome, Chronic Kidney, and Cardiovascular Diseases: Role of Adipokines

    Directory of Open Access Journals (Sweden)

    Manfredi Tesauro

    2011-01-01

    Full Text Available Obesity is a chronic disease, whose incidence is alarmingly growing. It is associated with metabolic abnormalities and cardiovascular complications. These complications are clustered in the metabolic syndrome (MetS leading to high cardiovascular morbidity and mortality. Obesity predisposes to diabetic nephropathy, hypertensive nephrosclerosis, and focal and segmental glomerular sclerosis and represents an independent risk factor for the development and progression of chronic kidney disease (CKD. Albuminuria is a major risk factor for cardiovascular diseases (CVDs. Microalbuminuria has been described as early manifestation of MetS-associated kidney damage and diabetic nephropathy. Obesity and MetS affect renal physiology and metabolism through mechanisms which include altered levels of adipokines such as leptin and adiponectin, oxidative stress, and inflammation. Secretory products of adipose tissue also deeply and negatively influence endothelial function. A better understanding of these interactions will help in designing more effective treatments aimed to protect both renal and cardiovascular systems.

  15. Relationship between the oral cavity and cardiovascular diseases and metabolic syndrome.

    Science.gov (United States)

    Carramolino-Cuéllar, Esther; Tomás, Inmaculada; Jiménez-Soriano, Yolanda

    2014-05-01

    The components of the human body are closely interdependent; as a result, disease conditions in some organs or components can influence the development of disease in other body locations. The effect of oral health upon health in general has been investigated for decades by many epidemiological studies. In this context, there appears to be a clear relationship between deficient oral hygiene and different systemic disorders such as cardiovascular disease and metabolic syndrome. The precise relationship between them is the subject of ongoing research, and a variety of theories have been proposed, though most of them postulate the mediation of an inflammatory response. This association between the oral cavity and disease in general requires further study, and health professionals should be made aware of the importance of adopting measures destined to promote correct oral health. The present study conducts a Medline search with the purpose of offering an update on the relationship between oral diseases and cardiovascular diseases, together with an evaluation of the bidirectional relationship between metabolic syndrome and periodontal disease. Most authors effectively describe a moderate association between the oral cavity and cardiovascular diseases, though they also report a lack of scientific evidence that oral alterations constitute an independent cause of cardiovascular diseases, or that their adequate treatment can contribute to prevent such diseases. In the case of metabolic syndrome, obesity and particularly diabetes mellitus may be associated to an increased susceptibility to periodontitis. However, it is not clear whether periodontal treatment is able to improve the systemic conditions of these patients.

  16. NAD+ metabolism in health and disease.

    Science.gov (United States)

    Belenky, Peter; Bogan, Katrina L; Brenner, Charles

    2007-01-01

    Nicotinamide adenine dinucleotide (NAD(+)) is both a coenzyme for hydride-transfer enzymes and a substrate for NAD(+)-consuming enzymes, which include ADP-ribose transferases, poly(ADP-ribose) polymerases, cADP-ribose synthases and sirtuins. Recent results establish protective roles for NAD(+) that might be applicable therapeutically to prevent neurodegenerative conditions and to fight Candida glabrata infection. In addition, the contribution that NAD(+) metabolism makes to lifespan extension in model systems indicates that therapies to boost NAD(+) might promote some of the beneficial effects of calorie restriction. Nicotinamide riboside, the recently discovered nucleoside precursor of NAD(+) in eukaryotic systems, might have advantages as a therapy to elevate NAD(+) without inhibiting sirtuins, which is associated with high-dose nicotinamide, or incurring the unpleasant side-effects of high-dose nicotinic acid.

  17. Latest data on metabolic diseases: Arterial Hypertension

    Directory of Open Access Journals (Sweden)

    Angelidi Angeliki

    2017-01-01

    Full Text Available Hypertension is closely related with increased cardiovascular risk and renal damage and its prevalence is even greater in elderly patients that are a highly heterogeneous group. The identification of hypertensive patients, as well as prompt initiation and timely titration of pharmacologic therapy in addition to lifestyle therapy in order to achieve blood pressure goals is of paramount importance. In general population, blood pressure goals of <140/90mmHg are recommended. However, treatment strategies and pharmacological therapy should be personalized depending on patient characteristics and comorbidities. Some drug agents or combinations should be considered as the preferential choice in specific conditions. However, the combination of two antagonists of the Renin Angiotensin System (RAS is not recommended and should be discouraged. In elderly hypertensives, it is recommended to reduce Systolic Blood Pressure (SBP between 150 and 140mmHg, provided they are in good physical and mental conditions, while a target of SBP <140mmHg may be considered, if treatment is also well tolerated. Lifestyle changes, and particularly weight loss and physical exercise, are to be recommended to all individuals with the metabolic syndrome. These interventions improve not only blood pressure, but the metabolic components of the syndrome. Antihypertensive agents that potentially improve or at least not worsen insulin sensitivity, such as RAS blockers and calcium antagonists, should be considered as the preferred drugs. Regarding patients with diabetes, lifestyle therapy and blood pressure goals of <140/90mmHg is generally recommended (American Diabetes Association, 2017. An ACE inhibitor or angiotensin receptor blocker, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and albuminuria. Taking into account several studies and meta-analyses recently published

  18. NF-κB, inflammation, and metabolic disease.

    Science.gov (United States)

    Baker, Rebecca G; Hayden, Matthew S; Ghosh, Sankar

    2011-01-05

    Metabolic disorders including obesity, type 2 diabetes, and atherosclerosis have been viewed historically as lipid storage disorders brought about by overnutrition. It is now widely appreciated that chronic low-grade inflammation plays a key role in the initiation, propagation, and development of metabolic diseases. Consistent with its central role in coordinating inflammatory responses, numerous recent studies have implicated the transcription factor NF-κB in the development of such diseases, thereby further establishing inflammation as a critical factor in their etiology and offering hope for the development of new therapeutic approaches for their treatment.

  19. Metabolic heat production by human and animal populations in cities

    Science.gov (United States)

    Stewart, Iain D.; Kennedy, Chris A.

    2016-12-01

    Anthropogenic heating from building energy use, vehicle fuel consumption, and human metabolism is a key term in the urban energy budget equation. Heating from human metabolism, however, is often excluded from urban energy budgets because it is widely observed to be negligible. Few reports for low-latitude cities are available to support this observation, and no reports exist on the contribution of domestic animals to urban heat budgets. To provide a more comprehensive view of metabolic heating in cities, we quantified all terms of the anthropogenic heat budget at metropolitan scale for the world's 26 largest cities, using a top-down statistical approach. Results show that metabolic heat release from human populations in mid-latitude cities (e.g. London, Tokyo, New York) accounts for 4-8% of annual anthropogenic heating, compared to 10-45% in high-density tropical cities (e.g. Cairo, Dhaka, Kolkata). Heat release from animal populations amounts to human and animal metabolism combined is highest in Mumbai—the world's most densely populated megacity—at 6.5 W m-2, surpassing heat production by electricity use in buildings (5.8 W m-2) and fuel combustion in vehicles (3.9 W m-2). These findings, along with recent output from global climate models, suggest that in the world's largest and most crowded cities, heat emissions from human metabolism alone can force measurable change in mean annual temperature at regional scale.

  20. Carbohydrate Metabolism in Bifidobacteria: Human Symbiotic Bacteria

    Science.gov (United States)

    Bifidobacterium ssp. constitute up to 90% of microbial gut flora in the infant colon, but considerably less in adults. Carbohydrate metabolism in these bacteria is highly unusual. Data from four Bifidobacterium genomes indicates genes missing from glycolysis, gluconeogenesis, and the TCA cycle, in...

  1. [Alzheimer's disease and human memory].

    Science.gov (United States)

    Eustache, F; Giffard, B; Rauchs, G; Chételat, G; Piolino, P; Desgranges, B

    2006-10-01

    Memory disorders observed in Alzheimer's disease gave rise, from the eighties, to a detailed analysis into the framework of cognitive neuropsychology which aimed at describing the deficits of very specific processes. Beyond their clinical interest, these studies contributed to the modelisation of human memory thanks to the characterization of different memory systems and their relationships. The first part of this paper gives an overview of the memory deficits in Alzheimer's disease and insists on particular cognitive phenomena. Hence, several examples are developed in the domains of semantic memory (such as hyperpriming and hypopriming effects) and autobiographical memory. Recent results highlight the existence of severe autobiographical amnesia observed in all neurodegenerative diseases, though with contrasting profiles: Ribot's gradient in Alzheimer's disease (showing that remote memories are better preserved than recent ones), reverse gradient in semantic dementia and no clear gradient in the frontal variant of frontotemporal dementia. The second part of this article presents advances in cognitive neuroscience searching to disclose the cerebral substrates of these cognitive deficits in Alzheimer's disease. The studies using functional imaging techniques are the most informative regarding this problematic. While showing the dysfunctions of an extended network, they emphasize the selectivity of cerebral damages that are at the root of very specific cognitive dysfunctions, coming close in that way to the conceptions of cognitive neuropsychology. These neuroimaging studies unravel the existence of compensatory mechanisms, which until recently were clearly missing in the literature on neurodegenerative diseases. These different researches lead to a wide conception of human memory, not just limited to simple instrumental processes (encoding, storage, retrieval), but necessarily covering models of identity and continuity of the subject, which interact in a dynamic way

  2. Mathematical modeling of the human energy metabolism based on the Selfish Brain Theory.

    Science.gov (United States)

    Chung, Matthias; Göbel, Britta

    2012-01-01

    Deregulations in the human energy metabolism may cause diseases such as obesity and type 2 diabetes mellitus. The origins of these pathologies are fairly unknown. The key role of the brain is the regulation of the complex whole body energy metabolism. The Selfish Brain Theory identifies the priority of brain energy supply in the competition for available energy resources within the organism. Here, we review mathematical models of the human energy metabolism supporting central aspects of the Selfish Brain Theory. First, we present a dynamical system modeling the whole body energy metabolism. This model takes into account the two central control mechanisms of the brain, i.e., allocation and appetite. Moreover, we present mathematical models of regulatory subsystems. We examine a neuronal model which specifies potential elements of the brain to sense and regulate cerebral energy content. We investigate a model of the HPA system regulating the allocation of energy within the organism. Finally, we present a robust modeling approach of appetite regulation. All models account for a systemic understanding of the human energy metabolism and thus do shed light onto defects causing metabolic diseases.

  3. Transfer RNA and human disease

    Directory of Open Access Journals (Sweden)

    Jamie A Abbott

    2014-06-01

    Full Text Available Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA genes are hotspots for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase, mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing. Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

  4. The interplay between intestinal bacteria and host metabolism in health and disease: lessons from Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Adam C. N. Wong

    2016-03-01

    Full Text Available All higher organisms negotiate a truce with their commensal microbes and battle pathogenic microbes on a daily basis. Much attention has been given to the role of the innate immune system in controlling intestinal microbes and to the strategies used by intestinal microbes to overcome the host immune response. However, it is becoming increasingly clear that the metabolisms of intestinal microbes and their hosts are linked and that this interaction is equally important for host health and well-being. For instance, an individual's array of commensal microbes can influence their predisposition to chronic metabolic diseases such as diabetes and obesity. A better understanding of host–microbe metabolic interactions is important in defining the molecular bases of these disorders and could potentially lead to new therapeutic avenues. Key advances in this area have been made using Drosophila melanogaster. Here, we review studies that have explored the impact of both commensal and pathogenic intestinal microbes on Drosophila carbohydrate and lipid metabolism. These studies have helped to elucidate the metabolites produced by intestinal microbes, the intestinal receptors that sense these metabolites, and the signaling pathways through which these metabolites manipulate host metabolism. Furthermore, they suggest that targeting microbial metabolism could represent an effective therapeutic strategy for human metabolic diseases and intestinal infection.

  5. Metabolic syndrome and chronic kidney disease in Okinawa, Japan.

    Science.gov (United States)

    Tanaka, H; Shiohira, Y; Uezu, Y; Higa, A; Iseki, K

    2006-01-01

    We assessed the prevalence of chronic kidney disease (CKD) in a hospital-based screening program in Okinawa, Japan. The significance of metabolic syndrome as a determinant of CKD was examined using multivariate logistic regression analysis. A total of 6980 participants, aged 30-79 years, participated in a screening program in Tomishiro Chuo Hospital. Metabolic syndrome was defined according to the criteria of the Adult Treatment Panel III (ATP III). Data were also analyzed according to the modified criteria of the National Cholesterol Education Program (NCEP) that defines abdominal obesity as a waist circumference of > oe =85 cm in men and > or =90 cm in women. CKD was defined as dipstick proteinuria (> or =1+) or a reduced glomerular filtration rate (GFR). GFR was estimated using the abbreviated Modification of Diet in Renal Disease (MDRD) formula. The prevalence of metabolic syndrome and CKD was 12.8 and 13.7%, respectively. Metabolic syndrome was a significant determinant of CKD (adjusted odds ratio (OR) 1.537 and 95% confidence interval (CI) 1.277-1.850, P or =60 years; OR 1.254, 95% CI 0.906-1.735, NS). The relationship between the number of metabolic syndrome risk factors and the prevalence of CKD was linear using the modified criteria. The results suggest that metabolic syndrome is a significant determinant of CKD in men under 60 years of age, in Okinawa, Japan.

  6. Endoplasmic reticulum-mitochondria calcium signaling in hepatic metabolic diseases.

    Science.gov (United States)

    Rieusset, Jennifer

    2017-06-01

    The liver plays a central role in glucose homeostasis, and both metabolic inflexibility and insulin resistance predispose to the development of hepatic metabolic diseases. Mitochondria and endoplasmic reticulum (ER), which play a key role in the control of hepatic metabolism, also interact at contact points defined as mitochondria-associated membranes (MAM), in order to exchange metabolites and calcium (Ca(2+)) and regulate cellular homeostasis and signaling. Here, we overview the role of the liver in the control of glucose homeostasis, mainly focusing on the independent involvement of mitochondria, ER and Ca(2+) signaling in both healthy and pathological contexts. Then we focus on recent data highlighting MAM as important hubs for hormone and nutrient signaling in the liver, thus adapting mitochondria physiology and cellular metabolism to energy availability. Lastly, we discuss how chronic ER-mitochondria miscommunication could participate to hepatic metabolic diseases, pointing MAM interface as a potential therapeutic target for metabolic disorders. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Mitochondria in metabolic disease: getting clues from proteomic studies.

    Science.gov (United States)

    Peinado, Juan R; Diaz-Ruiz, Alberto; Frühbeck, Gema; Malagon, Maria M

    2014-03-01

    Mitochondria play a key role as major regulators of cellular energy homeostasis, but in the context of mitochondrial dysfunction, mitochondria may generate reactive oxidative species and induce cellular apoptosis. Indeed, altered mitochondrial status has been linked to the pathogenesis of several metabolic disorders and specially disorders related to insulin resistance, such as obesity, type 2 diabetes, and other comorbidities comprising the metabolic syndrome. In the present review, we summarize information from various mitochondrial proteomic studies of insulin-sensitive tissues under different metabolic states. To that end, we first focus our attention on the pancreas, as mitochondrial malfunction has been shown to contribute to beta cell failure and impaired insulin release. Furthermore, proteomic studies of mitochondria obtained from liver, muscle, and adipose tissue are summarized, as these tissues constitute the primary insulin target metabolic tissues. Since recent advances in proteomic techniques have exposed the importance of PTMs in the development of metabolic disease, we also present information on specific PTMs that may directly affect mitochondria during the pathogenesis of metabolic disease. Specifically, mitochondrial protein acetylation, phosphorylation, and other PTMs related to oxidative damage, such as nitrosylation and carbonylation, are discussed. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

    Science.gov (United States)

    2017-06-27

    Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn; Alpha-Mannosidosis; Sanfilippo Mucopolysaccharidoses

  9. Mitochondrial Fusion Proteins and Human Diseases

    Directory of Open Access Journals (Sweden)

    Michela Ranieri

    2013-01-01

    Full Text Available Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1 and 2 (MFN2, located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1, in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer’s and Parkinson’s diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.

  10. Metabolic correction: a functional biochemical mechanism against disease--Part 1: concept and historical background.

    Science.gov (United States)

    González, Michael J; Miranda-Massari, Jorge R; Duconge, Jorge; Allende-Vigo, Myriam Z; Jiménez-Ramírez, Francisco J; Cintrón, Kenneth; Rodríguez-Gómez, Jose R; Rosario, Glorivee; Ricart, Carlos; Santiago-Cornier, Juan A; Zaragoza-Urdaz, Rafael; Vázquez, Alex; Hickey, Steve; Jabbar-Berdiel, Miguel; Riordan, Neil; Ichim, Thomas; Santiago, Oscar; Alvarado, Gilberto; Vora, Pramod

    2015-03-01

    Human physiology depends on countless biochemical reactions, numerous of which are co-dependent and interrelated. The speed and level of completion of reactions usually depend on the availability of precursors and enzymes. The enzymatic activity depends on the bioavailability of micronutrient cofactors such as vitamins and minerals. In order to achieve a healthy physiological state, the organism requires that biochemical reactions occur at a controlled rate. To achieve this state it is required that metabolic reactions reach what can be considered an optimal metabolic equilibrium. A combination of genetic makeup, dietary patterns, trauma, disease, toxins, medications, and environmental stressors can elevate the demand for the nutrients needed to reach this optimal metabolic equilibrium. In this, part 1, the general concept of metabolic correction is presented with an elaboration explaining how this concept is increasing in importance as we become aware of the presence of genetic variants that affect enzymatic reactions causing metabolic disturbances that themselves favor or promote the disease state. In addition, part 1 reviews how prominent scientists have contributed in fundamental ways to our understanding of the importance of micronutrients in health and disease and in the development of the metabolic correction concept.

  11. [Review on periodontal disease and metabolic control of diabetes mellitus].

    Science.gov (United States)

    Steffens, João Paulo; Glaci Reinke, Stella Maria; Angel Muñoz, Miguel; Santos, Fábio André dos; Luiz Pilatti, Gibson

    2010-09-01

    There may be an interaction between periodontal disease and some systemic diseases such as diabetes mellitus. The objective of this review was to verify, by means of a review of clinical trials, if there is a positive association between periodontal disease and the glycemic control of type 2 diabetes mellitus (DM-2) patients. Eleven articles that fi t the study criteria were revised. It was concluded that periodontal disease may influence the metabolic control of DM-2. Additional studies with larger sample sizes and longer follow up are necessary for a better clarification of this issue.

  12. Characterization of energy and neurotransmitter metabolism in cortical glutamatergic neurons derived from human induced pluripotent stem cells: A novel approach to study metabolism in human neurons.

    Science.gov (United States)

    Aldana, Blanca I; Zhang, Yu; Lihme, Maria Fog; Bak, Lasse K; Nielsen, Jørgen E; Holst, Bjørn; Hyttel, Poul; Freude, Kristine K; Waagepetersen, Helle S

    2017-02-24

    Alterations in the cellular metabolic machinery of the brain are associated with neurodegenerative disorders such as Alzheimer's disease. Novel human cellular disease models are essential in order to study underlying disease mechanisms. In the present study, we characterized major metabolic pathways in neurons derived from human induced pluripotent stem cells (hiPSC). With this aim, cultures of hiPSC-derived neurons were incubated with [U-(13)C]glucose, [U-(13)C]glutamate or [U-(13)C]glutamine. Isotopic labeling in metabolites was determined using gas chromatography coupled to mass spectrometry, and cellular amino acid content was quantified by high-performance liquid chromatography. Additionally, we evaluated mitochondrial function using real-time assessment of oxygen consumption via the Seahorse XF(e)96 Analyzer. Moreover, in order to validate the hiPSC-derived neurons as a model system, a metabolic profiling was performed in parallel in primary neuronal cultures of mouse cerebral cortex and cerebellum. These serve as well-established models of GABAergic and glutamatergic neurons, respectively. The hiPSC-derived neurons were previously characterized as being forebrain-specific cortical glutamatergic neurons. However, a comparable preparation of predominantly mouse cortical glutamatergic neurons is not available. We found a higher glycolytic capacity in hiPSC-derived neurons compared to mouse neurons and a substantial oxidative metabolism through the mitochondrial tricarboxylic acid (TCA) cycle. This finding is supported by the extracellular acidification and oxygen consumption rates measured in the cultured human neurons. [U-(13)C]Glutamate and [U-(13)C]glutamine were found to be efficient energy substrates for the neuronal cultures originating from both mice and humans. Interestingly, isotopic labeling in metabolites from [U-(13)C]glutamate was higher than that from [U-(13)C]glutamine. Although the metabolic profile of hiPSC-derived neurons in vitro was

  13. Metabolomics reveals metabolic biomarkers of Crohn's disease

    Energy Technology Data Exchange (ETDEWEB)

    Jansson, J.K.; Willing, B.; Lucio, M.; Fekete, A.; Dicksved, J.; Halfvarson, J.; Tysk, C.; Schmitt-Kopplin, P.

    2009-06-01

    The causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention.

  14. Metabolic syndrome as a risk factor for gallstone disease

    Institute of Scientific and Technical Information of China (English)

    Nahum Méndez-Sánchez; Norberto C. Chavez-Tapia; Daniel Motola-Kuba; Karla Sanchez-Lara; Guadalupe Ponciano-Rodríguez; Héctor Baptista; Martha H. Ramos; Misael Uribe

    2005-01-01

    AIM: To establish an association between the presence of metabolic syndrome and the development of gallstone disease.METHOIDS: We carried out a cross-sectional study in a check-up unit in a university hospital in Mexico City. We enrolled 245 subjects, comprising 65 subjects with gallstones (36 women, 29 men) and 180 controls (79women and 101 men without gallstones). Body mass index, waist circumference, blood pressure, plasma insulin, and serum lipids and lipoproteins levels were measured. Insulin resistance was calculated by homeostasis model assessment. Unconditional logistic regressionanalysis (univariate and multivariate) was used to calculate the risk of gallstone disease associated with the presence of at least three of the criteria (Adult Treatment Panel Ⅲ). Analyses were adjusted for age and sex.RESULTS: Among 245 subjects, metabolic syndrome was present in 40% of gallstone disease subjects, compared with 17.2% of the controls, adjusted by age and gender (odds ratio (OR) = 2.79; 95%CI, 1.46-5.33; P = 0.002),a dose-dependent effect was observed with each component of metabolic syndrome (OR = 2.36, 95%CI, 0.72-7.71;P = 0.16 with one component and OR = 5.54, 95%CI,1.35-22.74; P = 0.02 with four components of metabolic syndrome). Homeostasis model assessment was significantly associated with gallstone disease (adjusted OR = 2.25;95%CI, 1.08-4.69; P = 0.03).CONCLUSION: We conclude that as for cardiovascular disease and diabetes mellitus, gallstone disease appears to be strongly associated with metabolic syndrome.

  15. Metaflammation, NLRP3 Inflammasome Obesity and Metabolic Disease

    Directory of Open Access Journals (Sweden)

    Anna Meiliana

    2011-12-01

    Full Text Available BACKGROUND: Increasing prevalence of obesity gives rise to many problems associated with multiple morbidities, such as diabetes, hypertension, heart disease, sleep apnea and cancer. The mechanism of obesity is very complex, thus its link to various disease is poorly understood. This review highlights important concepts in our understanding of the pathogenesis of obesity and related complications. CONTENT: Many studies have tried to explore the exciting and puzzling links between metabolic homeostasis and inflammatory responses. A form of subclinical, low-grade systemic inflammation is known to be associated with both obesity and chronic disease. This, later called as "metaflammation", refers to metabolically triggered inflammation. The nutrient-sensing pathway and the immune response coordination are facilitated by these molecular sites in order to maintain homeostasis under diverse metabolic and immune conditions. Recent studies have found that the NLRP3 inflammasome during metabolic stress forms a tie linking TXNIP, oxidative stress, and IL-1β production. This provides new opportunities for research and therapy for the disease often described as the next global pandemic: type 2 diabetes mellitus (T2DM. SUMMARY: The crucial role of metaflammation in many complications of obesity shown by the unexpected overlap between inflammatory and metabolic sensors and their downstream tissue responses. Then great interest arose to explore the pathways that integrate nutrient and pathogen sensing, give more understanding in the mechanisms of insulin resistance type 2 diabetes, and other chronic metabolic pathologies. A family of intracellular sensors called NLR family is a critical component of the innate immune system. They can form multiprotein complexes, called inflammasome which is capable of responding to a wide range of stimuli including both microbial and self molecules by activating the cysteine protease caspase-1, leading to processing and

  16. The Relationship Between Sweeteners and Metabolic Diseases

    Directory of Open Access Journals (Sweden)

    Nildem Kızılaslan

    2017-02-01

    Full Text Available Sweeteners that sugar substitute is a food additive that provides a sweet taste like that of sugar while containing significantly less food energy. Some sugar substitutes are produced by nature, and others produced synthetically. Sweeteners can be classified as sugar alcohols (polyols, artificial sweeteners and natural sweeteners. The need to avoid the adverse effects of sugar cannot stop feeling the taste on humans has resulted in intense use of sweeteners nowadays. There are positive and negative opinions about the effects of their use on human health. The general tendency of food producers is to reduce the amount of sugar in the groats due to negative effects in parallel. Food sweeteners are intended for a large group of consumers, and one of the main points of the sector operators is to provide healthier, natural, nutritional and low calorie sweeteners to these consumers. In this study, we evaluated the sweeteners which are most commonly used. Many studies have been done to demonstrate the safety of sweeteners. There are also studies showing that there may be side effects even if there are few. Some sweeteners have been associated with a number of symptoms. There is a need for comparative long-term work in this area.

  17. P206-M Understanding the Metabolism of Amyloid-Beta in Humans

    OpenAIRE

    2007-01-01

    The most common form of dementia is Alzheimer’s disease. According to the amyloid hypothesis, the disease is preceded by an accumulation of the amyloid-β (Aβ) protein, which leads to downstream events including activation of microglia, inflammation, synaptic dysfunction, and neuronal loss. The objective of this research is to address the physiology of Aβ in humans by measuring its in vivo metabolic rates.

  18. Under- and overnutrition and evidence of metabolic disease risk in ...

    African Journals Online (AJOL)

    Under- and overnutrition and evidence of metabolic disease risk in rural black South ... Combined overweight and obesity prevalence was higher in the girls ... in the boys than in the girls in mid to late childhood in a rural setting in South Africa, ...

  19. [Metabolic bone disease in premature infants and genetic polymorphisms

    NARCIS (Netherlands)

    Funke, S.; Morava, E.; Czako, M.; Vida, G.; Ertl, T.; Kosztolanyi, G.Y.

    2007-01-01

    Metabolic bone disease is an important complication among infants very-low-birth-weight (< 1500 g). In adults, osteoporosis has been shown to be associated with polymorphisms of vitamin D receptor, estrogen receptor, and collagen Ialpha1 receptor genes. AIM: The primary goal of the study was to i

  20. INFORMATION SYSTEM FOR REGISTRY OF PATIENTS WITH METABOLIC DISEASES

    Directory of Open Access Journals (Sweden)

    N. H. Horovenko

    2015-05-01

    Full Text Available This article describes the problems encountered in the management of medical records of patients with metabolic diseases, and also provides a general solution to these problems through the introduction of a software product. Objective was to reduce the burden on the healthcare registrars and medical genetics center, improving the speed and quality of patient care. In the software implementation the main features of the complex design problems are described: the programming language Java, IDE NetBeans, MySQL database server and web application to work with database server phpMyAdmin and put forward requirements. Also, medical receptionist is able to keep track of patients to form an extract, view statistics. During development were numerous consultations with experienced doctors, medical registrars. With the convenient architecture in the future will be easy to add custom modules in the program. Development of the program management of electronic medical records of patients the center of metabolic diseases is essential, because today in Ukraine all the software that can keep track of patients who did not drawn enough attention to patients with metabolic diseases. Currently the software is installed in the center of metabolic diseases NCSH “OKHMATDYT.”

  1. Perfusion and metabolism imaging studies in Parkinson's disease

    DEFF Research Database (Denmark)

    Borghammer, Per

    2012-01-01

    Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are important tools in the evaluation of brain blood flow and glucose metabolism in Parkinson's disease (PD). However, conflicting results are reported in the literature depending on the type of imaging data...

  2. Effect of Natural Polyphenols on CYP Metabolism: Implications for Diseases.

    Science.gov (United States)

    Korobkova, Ekaterina A

    2015-07-20

    Cytochromes P450 (CYPs) are a large group of hemeproteins located on mitochondrial membranes or the endoplasmic reticulum. They play a crucial role in the metabolism of endogenous and exogenous molecules. The activity of CYP is associated with a number of factors including redox potential, protein conformation, the accessibility of the active site by substrates, and others. This activity may be potentially modulated by a variety of small molecules. Extensive experimental data collected over the past decade point at the active role of natural polyphenols in modulating the catalytic activity of CYP. Polyphenols are widespread micronutrients present in human diets of plant origin and in medicinal herbs. These compounds may alter the activity of CYP either via direct interactions with the enzymes or by affecting CYP gene expression. The polyphenol-CYP interactions may significantly alter the pharmacokinetics of drugs and thus influence the effectiveness of chemical therapies used in the treatment of different types of cancers, diabetes, obesity, and cardiovascular diseases (CVD). CYPs are involved in the oxidation and activation of external carcinogenic agents, in which case the inhibition of the CYP activity is beneficial for health. CYPs also support detoxification processes. In this case, it is the upregulation of CYP genes that would be favorable for the organism. A CYP enzyme aromatase catalyzes the formation of estrone and estradiol from their precursors. CYPs also catalyze multiple reactions leading to the oxidation of estrogen. Estrogen signaling and oxidative metabolism of estrogen are associated with the development of cancer. Thus, polyphenol-mediated modulation of the CYP's activity also plays a vital role in estrogen carcinogenesis. The aim of the present review is to summarize the data collected over the last five to six years on the following topics: (1) the mechanisms of the interactions of CYP with food constituents that occur via the direct binding of

  3. Targeting Adipose Tissue Lipid Metabolism to Improve Glucose Metabolism in Cardiometabolic Disease

    OpenAIRE

    Jocken, Johan W. E.; Goossens, Gijs H.; Blaak, Ellen E.

    2014-01-01

    With Type 2 diabetes mellitus and cardiovascular disease prevalence on the rise, there is a growing need for improved strategies to prevent or treat obesity and insulin resistance, both of which are major risk factors for these chronic diseases. Impairments in adipose tissue lipid metabolism seem to play a critical role in these disorders. In the classical picture of intracellular lipid breakdown, cytosolic lipolysis was proposed as the sole mechanism for triacylglycerol hydrolysis in adipocy...

  4. Is butyrate the link between diet, intestinal microbiota and obesity-related metabolic diseases?

    Science.gov (United States)

    Brahe, L K; Astrup, A; Larsen, L H

    2013-12-01

    It is increasingly recognized that there is a connection between diet, intestinal microbiota, intestinal barrier function and the low-grade inflammation that characterizes the progression from obesity to metabolic disturbances, making dietary strategies to modulate the intestinal environment relevant. In this context, the ability of some Gram-positive anaerobic bacteria to produce the short-chain fatty acid butyrate is interesting. A lower abundance of butyrate-producing bacteria has been associated with metabolic risk in humans, and recent studies suggest that butyrate might have an anti-inflammatory potential that can alleviate obesity-related metabolic complications, possibly due to its ability to enhance the intestinal barrier function. Here, we review and discuss the potential of butyrate as an anti-inflammatory mediator in metabolic diseases, and the potential for dietary interventions increasing the intestinal availability of butyrate.

  5. Dietary fatty acids in metabolic syndrome, diabetes and cardiovascular diseases.

    Science.gov (United States)

    Cascio, Giuseppe; Schiera, Gabriella; Di Liegro, Italia

    2012-01-01

    In the last few decades, the prevalence of overweight and essential obesity has been undergoing a fast and progressive worldwide increase. Obesity has been in turn linked to type II diabetes, with the total number of diabetic patients worryingly increasing, in the last fifteen years, suggesting a pandemic phenomenon. At the same time, an increase in the prevalence of cardiovascular diseases has been also recorded. Increasing evidence suggests that the diet is involved in such escalation. In particular, the progressive globalization of food industry allowed massive supply, at a relatively low price, of a great variety of pre-packed food and bakery products, with very high energy content. Most of this food contains high amounts of saturated fatty acids (SFA) and of hydrogenated or trans fatty acids (TFA), that probably represent the prominent risk factors in the diet. Herein we will report diffusion and possible impact on health of such molecules, with reference to coronary heart disease, insulin resistance, metabolic syndrome and diabetes. We will also discuss the cellular and molecular mechanisms of action of fatty acids and fatty acid-derivatives which have been involved either in promoting or in preventing human pathologies. Free fatty acids (FFA) are not indeed only essential fuels for the organism. They also act as ligands for both membrane and nuclear receptors involved in different signaling pathways. Notably, some of these pathways can induce cell stress and apoptosis. Most important, FFA can affect glucose-induced insulin secretion and activate β-cell death. These events can be at least in part counteracted by polyunsaturated fatty acids.

  6. Metabolic disorders and nutritional status in autoimmune thyroid diseases

    Directory of Open Access Journals (Sweden)

    Anna Kawicka

    2015-01-01

    Full Text Available In recent years, the authors of epidemiological studies have documented that autoimmune diseases are a major problem of modern society and are classified as diseases of civilization. Autoimmune thyroid diseases (ATDs are caused by an abnormal immune response to autoantigens present in the thyroid gland – they often coexist with other autoimmune diseases. The most common dysfunctions of the thyroid gland are hypothyroidism, Graves-Basedow disease and Hashimoto’s disease. Hashimoto’s thyroiditis can be the main cause of primary hypothyroidism of the thyroid gland. Anthropometric, biochemical and physicochemical parameters are used to assess the nutritional status during the diagnosis and treatment of thyroid diseases. Patients with hypothyroidism are often obese, whereas patients with hyperthyroidism are often afflicted with rapid weight loss. The consequence of obesity is a change of the thyroid hormones’ activity; however, weight reduction leads to their normalization. The activity and metabolic rate of thyroid hormones are modifiable. ATDs are associated with abnormalities of glucose metabolism and thus increased risk of developing diabetes mellitus type 1 and type 2. Celiac disease (CD also increases the risk of developing other autoimmune diseases. Malnutrition or the presence of numerous nutritional deficiencies in a patient’s body can be the cause of thyroid disorders. Coexisting deficiencies of such elements as iodine, iron, selenium and zinc may impair the function of the thyroid gland. Other nutrient deficiencies usually observed in patients suffering from ATD are: protein deficiencies, vitamin deficiencies (A, C, B6, B5, B1 and mineral deficiencies (phosphorus, magnesium, potassium, sodium, chromium. Proper diet helps to reduce the symptoms of the disease, maintains a healthy weight and prevents the occurrence of malnutrition. This article presents an overview of selected documented studies and scientific reports on the

  7. [Metabolic disorders and nutritional status in autoimmune thyroid diseases].

    Science.gov (United States)

    Kawicka, Anna; Regulska-Ilow, Bożena; Regulska-Ilow, Bożena

    2015-01-02

    In recent years, the authors of epidemiological studies have documented that autoimmune diseases are a major problem of modern society and are classified as diseases of civilization. Autoimmune thyroid diseases (ATDs) are caused by an abnormal immune response to autoantigens present in the thyroid gland - they often coexist with other autoimmune diseases. The most common dysfunctions of the thyroid gland are hypothyroidism, Graves-Basedow disease and Hashimoto's disease. Hashimoto's thyroiditis can be the main cause of primary hypothyroidism of the thyroid gland. Anthropometric, biochemical and physicochemical parameters are used to assess the nutritional status during the diagnosis and treatment of thyroid diseases. Patients with hypothyroidism are often obese, whereas patients with hyperthyroidism are often afflicted with rapid weight loss. The consequence of obesity is a change of the thyroid hormones' activity; however, weight reduction leads to their normalization. The activity and metabolic rate of thyroid hormones are modifiable. ATDs are associated with abnormalities of glucose metabolism and thus increased risk of developing diabetes mellitus type 1 and type 2. Celiac disease (CD) also increases the risk of developing other autoimmune diseases. Malnutrition or the presence of numerous nutritional deficiencies in a patient's body can be the cause of thyroid disorders. Coexisting deficiencies of such elements as iodine, iron, selenium and zinc may impair the function of the thyroid gland. Other nutrient deficiencies usually observed in patients suffering from ATD are: protein deficiencies, vitamin deficiencies (A, C, B6, B5, B1) and mineral deficiencies (phosphorus, magnesium, potassium, sodium, chromium). Proper diet helps to reduce the symptoms of the disease, maintains a healthy weight and prevents the occurrence of malnutrition. This article presents an overview of selected documented studies and scientific reports on the relationship of metabolic

  8. Evidence for a metabolic shift of arginine metabolism in sickle cell disease

    NARCIS (Netherlands)

    Schnog, JJB; Jager, EH; van der Dijs, FPL; Duits, AJ; Moshage, H; Muskiet, FD; Muskiet, FAJ

    2004-01-01

    Over the last few years, a pivotal role has been ascribed to reduced nitric oxide (NO) availability as a contributing factor to the vaso-occlusive process of sickle cell disease. We investigated whether arginine metabolism in sickle cell patients is different from healthy controls. Blood samples wer

  9. Evidence for a metabolic shift of arginine metabolism in sickle cell disease

    NARCIS (Netherlands)

    Schnog, JJB; Jager, EH; van der Dijs, FPL; Duits, AJ; Moshage, H; Muskiet, FD; Muskiet, FAJ

    2004-01-01

    Over the last few years, a pivotal role has been ascribed to reduced nitric oxide (NO) availability as a contributing factor to the vaso-occlusive process of sickle cell disease. We investigated whether arginine metabolism in sickle cell patients is different from healthy controls. Blood samples wer

  10. Impact of high cholesterol and endoplasmic reticulum stress on metabolic diseases: An updated mini-review

    Directory of Open Access Journals (Sweden)

    Erdi Sozen

    2017-08-01

    Full Text Available Endoplasmic reticulum (ER is the major site of protein folding and calcium storage. Beside the role of ER in protein homeostasis, it controls the cholesterol production and lipid-membrane biosynthesis as well as surviving and cell death signaling mechanisms in the cell. It is well-documented that elevated plasma cholesterol induces adverse effects in cardiovascular diseases (CVDs, liver disorders, such as non-alcoholic fatty liver disease (NAFLD, non-alcoholic steatosis hepatitis (NASH, and metabolic diseases which are associated with oxidative and ER stress. Recent animal model and human studies have showed high cholesterol and ER stress as an emerging factors involved in the development of many metabolic diseases. In this review, we will summarize the crucial effects of hypercholesterolemia and ER stress response in the pathogenesis of CVDs, NAFLD/NASH, diabetes and obesity which are major health problems in western countries.

  11. CardioNet: A human metabolic network suited for the study of cardiomyocyte metabolism

    Directory of Open Access Journals (Sweden)

    Karlstädt Anja

    2012-08-01

    Full Text Available Abstract Background Availability of oxygen and nutrients in the coronary circulation is a crucial determinant of cardiac performance. Nutrient composition of coronary blood may significantly vary in specific physiological and pathological conditions, for example, administration of special diets, long-term starvation, physical exercise or diabetes. Quantitative analysis of cardiac metabolism from a systems biology perspective may help to a better understanding of the relationship between nutrient supply and efficiency of metabolic processes required for an adequate cardiac output. Results Here we present CardioNet, the first large-scale reconstruction of the metabolic network of the human cardiomyocyte comprising 1793 metabolic reactions, including 560 transport processes in six compartments. We use flux-balance analysis to demonstrate the capability of the network to accomplish a set of 368 metabolic functions required for maintaining the structural and functional integrity of the cell. Taking the maintenance of ATP, biosynthesis of ceramide, cardiolipin and further important phospholipids as examples, we analyse how a changed supply of glucose, lactate, fatty acids and ketone bodies may influence the efficiency of these essential processes. Conclusions CardioNet is a functionally validated metabolic network of the human cardiomyocyte that enables theorectical studies of cellular metabolic processes crucial for the accomplishment of an adequate cardiac output.

  12. Part 1: The Human Gut Microbiome in Health and Disease

    OpenAIRE

    Bull, Matthew J.; Plummer, Nigel T.

    2014-01-01

    The bacterial cells harbored within the human gastrointestinal tract (GIT) outnumber the host’s cells by a factor of 10 and the genes encoded by the bacteria resident within the GIT outnumber their host’s genes by more than 100 times. These human digestive-tract associated microbes are referred to as the gut microbiome. The human gut microbiome and its role in both health and disease has been the subject of extensive research, establishing its involvement in human metabolism, nutrition, physi...

  13. Human Microbiota and Ophthalmic Disease.

    Science.gov (United States)

    Lu, Louise J; Liu, Ji

    2016-09-01

    The human ocular surface, consisting of the cornea and conjunctiva, is colonized by an expansive, diverse microbial community. Molecular-based methods, such as 16S rRNA sequencing, has allowed for more comprehensive and precise identification of the species composition of the ocular surface microbiota compared to traditional culture-based methods. Evidence suggests that the normal microbiota plays a protective immunological role in preventing the proliferation of pathogenic species and thus, alterations in the homeostatic microbiome may be linked to ophthalmic pathologies. Further investigation of the ocular surface microbiome, as well as the microbiome of other areas of the body such as the oral mucosa and gut, and their role in the pathophysiology of diseases is a significant, emerging field of research, and may someday enable the development of novel probiotic approaches for the treatment and prevention of ophthalmic diseases.

  14. Human Cytomegalovirus and Autoimmune Disease

    Directory of Open Access Journals (Sweden)

    Anne Halenius

    2014-01-01

    Full Text Available Human cytomegalovirus (HCMV represents a prototypic pathogenic member of the β-subgroup of the herpesvirus family. A range of HCMV features like its lytic replication in multiple tissues, the lifelong persistence through periods of latency and intermitting reactivation, the extraordinary large proteome, and extensive manipulation of adaptive and innate immunity make HCMV a high profile candidate for involvement in autoimmune disorders. We surveyed the available literature for reports on HCMV association with onset or exacerbation of autoimmune disease. A causative linkage between HCMV and systemic lupus erythematosus (SLE, systemic sclerosis (SSc, diabetes mellitus type 1, and rheumatoid arthritis (RA is suggested by the literature. However, a clear association of HCMV seroprevalence and disease could not be established, leaving the question open whether HCMV could play a coresponsible role for onset of disease. For convincing conclusions population-based prospective studies must be performed in the future. Specific immunopathogenic mechanisms by which HCMV could contribute to the course of autoimmune disease have been suggested, for example, molecular mimicry by UL94 in SSc and UL83/pp65 in SLE patients, as well as aggravation of joint inflammation by induction and expansion of CD4+/CD28− T-cells in RA patients. Further studies are needed to validate these findings and to lay the grounds for targeted therapeutic intervention.

  15. Xenobiotic metabolism in human skin and 3D human skin reconstructs: A review

    NARCIS (Netherlands)

    Gibbs, S.; Sandt, J.J.M. van de; Merk, H.F.; Lockley, D.J.; Pendlington, R.U.; Pease, C.K.

    2007-01-01

    In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental

  16. Xenobiotic metabolism in human skin and 3D human skin reconstructs: A review

    NARCIS (Netherlands)

    Gibbs, S.; Sandt, J.J.M. van de; Merk, H.F.; Lockley, D.J.; Pendlington, R.U.; Pease, C.K.

    2007-01-01

    In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental

  17. Aluminium and human breast diseases.

    Science.gov (United States)

    Darbre, P D; Pugazhendhi, D; Mannello, F

    2011-11-01

    The human breast is exposed to aluminium from many sources including diet and personal care products, but dermal application of aluminium-based antiperspirant salts provides a local long-term source of exposure. Recent measurements have shown that aluminium is present in both tissue and fat of the human breast but at levels which vary both between breasts and between tissue samples from the same breast. We have recently found increased levels of aluminium in noninvasively collected nipple aspirate fluids taken from breast cancer patients (mean 268 ± 28 μg/l) compared with control healthy subjects (mean 131 ± 10 μg/l) providing evidence of raised aluminium levels in the breast microenvironment when cancer is present. The measurement of higher levels of aluminium in type I human breast cyst fluids (median 150 μg/l) compared with human serum (median 6 μg/l) or human milk (median 25 μg/l) warrants further investigation into any possible role of aluminium in development of this benign breast disease. Emerging evidence for aluminium in several breast structures now requires biomarkers of aluminium action in order to ascertain whether the presence of aluminium has any biological impact. To this end, we report raised levels of proteins that modulate iron homeostasis (ferritin, transferrin) in parallel with raised aluminium in nipple aspirate fluids in vivo, and we report overexpression of mRNA for several S100 calcium binding proteins following long-term exposure of MCF-7 human breast cancer cells in vitro to aluminium chlorhydrate.

  18. Manipulating the circadian and sleep cycles to protect against metabolic disease

    Directory of Open Access Journals (Sweden)

    Kazunari eNohara

    2015-03-01

    Full Text Available Modernization of human society parallels an epidemic of metabolic disorders including obesity. Apart from excess caloric intake, a 24/7 lifestyle poses another important challenge to our metabolic health. Recent research under both laboratory and epidemiological settings has indicated that abnormal temporal organization of sleep and wakeful activities including food intake is a significant risk factor for metabolic disease. The circadian clock system is our intrinsic biological timer that regulates internal rhythms such as the sleep/wake cycle and also responses to external stimuli including light and food. Initially thought to be mainly involved in the timing of sleep, the clock and/or clock genes may also play a role in sleep architecture and homeostasis. Importantly, an extensive body of evidence has firmly established a master regulatory role of the clock in energy balance. Together, a close relationship between well-timed circadian/sleep cycles and metabolic health is emerging. Exploiting this functional connection, an important holistic strategy toward curbing the epidemic of metabolic disorders (e.g. obesity involves corrective measures on the circadian clock and sleep. In addition to behavioral and environmental interventions including meal timing and light control, pharmacological agents targeting sleep and circadian clocks promise convenient and effective applications. Recent studies, for example, have reported small molecules targeting specific clock components and displaying robust beneficial effects on sleep and metabolism. Furthermore, a group of clock-amplitude enhancing small molecules (CEMs identified via high-throughput chemical screens are of particular interest for future in vivo studies of their metabolic and sleep efficacies. Elucidating the functional relationship between clock, sleep and metabolism will also have far-reaching implications for various chronic human diseases and aging.

  19. Manipulating the circadian and sleep cycles to protect against metabolic disease.

    Science.gov (United States)

    Nohara, Kazunari; Yoo, Seung-Hee; Chen, Zheng Jake

    2015-01-01

    Modernization of human society parallels an epidemic of metabolic disorders including obesity. Apart from excess caloric intake, a 24/7 lifestyle poses another important challenge to our metabolic health. Recent research under both laboratory and epidemiological settings has indicated that abnormal temporal organization of sleep and wakeful activities including food intake is a significant risk factor for metabolic disease. The circadian clock system is our intrinsic biological timer that regulates internal rhythms such as the sleep/wake cycle and also responses to external stimuli including light and food. Initially thought to be mainly involved in the timing of sleep, the clock, and/or clock genes may also play a role in sleep architecture and homeostasis. Importantly, an extensive body of evidence has firmly established a master regulatory role of the clock in energy balance. Together, a close relationship between well-timed circadian/sleep cycles and metabolic health is emerging. Exploiting this functional connection, an important holistic strategy toward curbing the epidemic of metabolic disorders (e.g., obesity) involves corrective measures on the circadian clock and sleep. In addition to behavioral and environmental interventions including meal timing and light control, pharmacological agents targeting sleep and circadian clocks promise convenient and effective applications. Recent studies, for example, have reported small molecules targeting specific clock components and displaying robust beneficial effects on sleep and metabolism. Furthermore, a group of clock-amplitude-enhancing small molecules (CEMs) identified via high-throughput chemical screens are of particular interest for future in vivo studies of their metabolic and sleep efficacies. Elucidating the functional relationship between clock, sleep, and metabolism will also have far-reaching implications for various chronic human diseases and aging.

  20. Metabolic fate of extracted glucose in normal human myocardium.

    OpenAIRE

    Wisneski, J A; Gertz, E W; Neese, R A; Gruenke, L D; D. L. Morris; Craig, J. C.

    1985-01-01

    Glucose is an important substrate for myocardial metabolism. This study was designed to determine the effect of circulating metabolic substrates on myocardial glucose extraction and to determine the metabolic fate of glucose in normal human myocardium. Coronary sinus and arterial catheters were placed in 23 healthy male volunteers. [6-14C]Glucose was infused as a tracer in 10 subjects. [6-14C]Glucose and [U-13C]lactate were simultaneously infused in the other 13 subjects. Simultaneous blood s...

  1. Phytanic acid metabolism in health and disease.

    Science.gov (United States)

    Wanders, Ronald J A; Komen, Jasper; Ferdinandusse, Sacha

    2011-09-01

    Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid which cannot be beta-oxidized due to the presence of the first methyl group at the 3-position. Instead, phytanic acid undergoes alpha-oxidation to produce pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) plus CO(2). Pristanic acid is a 2-methyl branched-chain fatty acid which can undergo beta-oxidation via sequential cycles of beta-oxidation in peroxisomes and mitochondria. The mechanism of alpha-oxidation has been resolved in recent years as reviewed in this paper, although some of the individual enzymatic steps remain to be identified. Furthermore, much has been learned in recent years about the permeability properties of the peroxisomal membrane with important consequences for the alpha-oxidation process. Finally, we present new data on the omega-oxidation of phytanic acid making use of a recently generated mouse model for Refsum disease in which the gene encoding phytanoyl-CoA 2-hydroxylase has been disrupted.

  2. Metabolic syndrome in inflammatory rheumatic diseases

    Directory of Open Access Journals (Sweden)

    G. La Montagna

    2011-09-01

    Full Text Available Toward the end of the last century a better knowledge of cardiovascular (CV risk factors and their associations led investigators to propose the existence of a unique pathophysiological condition called “metabolic” or “insulin resistance syndrome”. Among all, insulin-resistance and compensatory hyperinsulinemia are considered its most important treatment targets. Different definitions have been provided by World Health Organization (WHO and by The Third Report of The National Cholesterol Education Program’s Adult Treatment Panel (NCEP-ATP III. In particular, abdominal obesity, hypertension, low HDL cholesterol and hyperglicemia are the most common items used for its definition. The presence of MetS is effective in predicting the future risk of diabetes and coronaropathies. The evidence of a higher CV risk rate among different rheumatic inflammatory diseases has recently been associated with high prevalence of MetS in some cases. Rheumatoid or psoriatic arthritis have the large series among arthritis, whereas systemic lupus erythematosus among connective tissue disorders. This review analyses all most important studies about the evidence of MetS in rheumatic patients and the main clinical and prognostic significance of this relation.

  3. [End stage of chronic kidney disease and metabolic acidosis].

    Science.gov (United States)

    Klaboch, J; Opatrná, S; Matoušovic, K; Schück, O

    2012-01-01

    Renal function disorder is inevitably associated with metabolic acidosis. An adult produces approximately 1 mmol of acids/kg of body weight every day (3 mmol/kg in children), derived from metabolization of proteins from food. Development of metabolic acidosis in patients with kidney disease is based on accumulation of acids and insufficient production of bicarbonates; alkaline loss represents a marginal issue here limited to patients with type II renal tubular acidosis only. The prevalence of this disorder increases with declining glomerular filtration (GFR) from 2% in patients with GFR 1.0-1.5 ml/s/1.73 m2 to 39% in patients with GFR inflammation, to progression of tubular interstitial fibrosis that subsequently leads to further GFR reduction. Metabolic acidosis has a number of severe adverse effects on the organism, e.g. deterioration of kidney bone disease through stimulation of bone resorption and inhibition of bone formation, inhibition of vitamin D formation, increased muscle catabolism, reduced albumin production, glucose metabolism disorder, increased insulin resistance, reduced production of thyroid hormones, increased accumulation of β2-microglobulin etc. Non-interventional studies suggest that alkali supplementation may slow down progression of chronic nephropathies. However, this approach, safe and inexpensive, has not been widely implemented in clinical practice yet. With respect to dialyzed patients, abnormal levels of bicarbonates are associated with increased mortality. Both metabolic acidosis and alkalosis, rather regularly seen in a considerable number of patients, have a negative effect on patient survival. Alkali substitution from a dialysis solution is the main pillar of metabolic acidosis management in patients on hemo- as well as peritoneal dialysis. Available technologies allow individualization of the treatment and this should be observed.

  4. Adrenergic Receptors and Metabolism: Role in development of cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Michele eCiccarelli

    2013-10-01

    Full Text Available Activation of the adrenergic system has a profound effects on metabolism. Increased circulating catecholamine and activation of the different adrenergic receptors deployed in the various organs produce important metabolic responses which include: 1 increased lipolysis and elevated levels of fatty acids in plasma, 2 increased gluconeogenesis by the liver to provide substrate for the brain and 3 moderate inhibition of insulin release by the pancreas to conserve glucose and to shift fuel metabolism of muscle in the direction of fatty acid oxidation. These physiological responses, typical of the stress conditions, are demonstrated to be detrimental for the functioning of different organs like the cardiac muscle when they become chronic. Indeed, a common feature of many pathological conditions involving over-activation of the adrenergic system is the development of metabolic alterations which can include insulin resistance, altered glucose and lipid metabolism and mitochondrial dysfunction. These patterns are involved with a variably extent among the different pathologies , however they are in general strictly correlated to the level of activation of the adrenergic system. Here we will review the effects of the different adrenergic receptors subtypes on the metabolic variation observed in important disease like Heart Failure.

  5. Metabolic state alters economic decision making under risk in humans.

    Directory of Open Access Journals (Sweden)

    Mkael Symmonds

    Full Text Available BACKGROUND: Animals' attitudes to risk are profoundly influenced by metabolic state (hunger and baseline energy stores. Specifically, animals often express a preference for risky (more variable food sources when below a metabolic reference point (hungry, and safe (less variable food sources when sated. Circulating hormones report the status of energy reserves and acute nutrient intake to widespread targets in the central nervous system that regulate feeding behaviour, including brain regions strongly implicated in risk and reward based decision-making in humans. Despite this, physiological influences per se have not been considered previously to influence economic decisions in humans. We hypothesised that baseline metabolic reserves and alterations in metabolic state would systematically modulate decision-making and financial risk-taking in humans. METHODOLOGY/PRINCIPAL FINDINGS: We used a controlled feeding manipulation and assayed decision-making preferences across different metabolic states following a meal. To elicit risk-preference, we presented a sequence of 200 paired lotteries, subjects' task being to select their preferred option from each pair. We also measured prandial suppression of circulating acyl-ghrelin (a centrally-acting orexigenic hormone signalling acute nutrient intake, and circulating leptin levels (providing an assay of energy reserves. We show both immediate and delayed effects on risky decision-making following a meal, and that these changes correlate with an individual's baseline leptin and changes in acyl-ghrelin levels respectively. CONCLUSIONS/SIGNIFICANCE: We show that human risk preferences are exquisitely sensitive to current metabolic state, in a direction consistent with ecological models of feeding behaviour but not predicted by normative economic theory. These substantive effects of state changes on economic decisions perhaps reflect shared evolutionarily conserved neurobiological mechanisms. We suggest that

  6. Metabolic Bone Disease in the Bariatric Surgery Patient

    Directory of Open Access Journals (Sweden)

    Susan E. Williams

    2011-01-01

    Full Text Available Bariatric surgery has proven to be a life-saving measure for some, but for others it has precipitated a plethora of metabolic complications ranging from mild to life-threatening, sometimes to the point of requiring surgical revision. Obesity was previously thought to be bone protective, but this is indeed not the case. Morbidly obese individuals are at risk for metabolic bone disease (MBD due to chronic vitamin D deficiency, inadequate calcium intake, sedentary lifestyle, chronic dieting, underlying chronic diseases, and the use of certain medications used to treat those diseases. After bariatric surgery, the risk for bone-related problems is even greater, owing to severely restricted intake, malabsorption, poor compliance with prescribed supplements, and dramatic weight loss. Patients presenting for bariatric surgery should be evaluated for MBD and receive appropriate presurgical interventions. Furthermore, every patient who has undergone bariatric surgery should receive meticulous lifetime monitoring, as the risk for developing MBD remains ever present.

  7. Analyzing the regulation of metabolic pathways in human breast cancer

    Directory of Open Access Journals (Sweden)

    Schramm Gunnar

    2010-09-01

    Full Text Available Abstract Background Tumor therapy mainly attacks the metabolism to interfere the tumor's anabolism and signaling of proliferative second messengers. However, the metabolic demands of different cancers are very heterogeneous and depend on their origin of tissue, age, gender and other clinical parameters. We investigated tumor specific regulation in the metabolism of breast cancer. Methods For this, we mapped gene expression data from microarrays onto the corresponding enzymes and their metabolic reaction network. We used Haar Wavelet transforms on optimally arranged grid representations of metabolic pathways as a pattern recognition method to detect orchestrated regulation of neighboring enzymes in the network. Significant combined expression patterns were used to select metabolic pathways showing shifted regulation of the aggressive tumors. Results Besides up-regulation for energy production and nucleotide anabolism, we found an interesting cellular switch in the interplay of biosynthesis of steroids and bile acids. The biosynthesis of steroids was up-regulated for estrogen synthesis which is needed for proliferative signaling in breast cancer. In turn, the decomposition of steroid precursors was blocked by down-regulation of the bile acid pathway. Conclusion We applied an intelligent pattern recognition method for analyzing the regulation of metabolism and elucidated substantial regulation of human breast cancer at the interplay of cholesterol biosynthesis and bile acid metabolism pointing to specific breast cancer treatment.

  8. [Carbohydrate: current role in diabetes mellitus and metabolic disease].

    Science.gov (United States)

    Luna López, Victoria; López Medina, José Antonio; Vázquez Gutiérrez, Mercedes; Fernández Soto, M Luisa

    2014-11-01

    There is a prevalence of diabetes mellitus (DM), unknown DM and stress hyperglycemia among hospital patients, and the nutritional treatment is a key part of care, where carbohydrates (CH) intake is a controversial issue. There is also a discussion on the increase of prevalence for DM, obesity and metabolic disease with refined CH or sugar. This review examines the recommendations from different scientific societies about the percentage of CH in the total calorie intake of the diabetic patient, the CH value in the glycemic index and glycemic load, the new CH included in enteral formulae and the association of refined CH with the high prevalence of DM and metabolic disease. Systematic review of literature using the electronic scientific databases Pubmed, Science Direct, Scielo, Scopus and Medline. Scientific societies are flexible about the CH intake in the diet of diabetic patients, suggesting to customize it according to each metabolic profile. Using the glycemic index and glycemic load can provide an extra benefit in the postprandial glycemic control. The new diabetes-specific enteral formulae, with fructooligosaccharides, resistant maltodextrins and fructose-free show efficacy in improving the glycemic control, although more controlled and long-term studies are needed. There is still some controversy about the links between sugar intake and DM, obesity and metabolic disease, although this relationship would be more linked to an increase of the total calorie intake than to a specific nutrient. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  9. Understanding specificity in metabolic pathways--structural biology of human nucleotide metabolism.

    Science.gov (United States)

    Welin, Martin; Nordlund, Pär

    2010-05-21

    Interactions are the foundation of life at the molecular level. In the plethora of activities in the cell, the evolution of enzyme specificity requires the balancing of appropriate substrate affinity with a negative selection, in order to minimize interactions with other potential substrates in the cell. To understand the structural basis for enzyme specificity, the comparison of structural and biochemical data between enzymes within pathways using similar substrates and effectors is valuable. Nucleotide metabolism is one of the largest metabolic pathways in the human cell and is of outstanding therapeutic importance since it activates and catabolises nucleoside based anti-proliferative drugs and serves as a direct target for anti-proliferative drugs. In recent years the structural coverage of the enzymes involved in human nucleotide metabolism has been dramatically improved and is approaching completion. An important factor has been the contribution from the Structural Genomics Consortium (SGC) at Karolinska Institutet, which recently has solved 33 novel structures of enzymes and enzyme domains in human nucleotide metabolism pathways and homologs thereof. In this review we will discuss some of the principles for substrate specificity of enzymes in human nucleotide metabolism illustrated by a selected set of enzyme families where a detailed understanding of the structural determinants for specificity is now emerging.

  10. Understanding specificity in metabolic pathways-Structural biology of human nucleotide metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Welin, Martin [Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm (Sweden); Nordlund, Paer, E-mail: Par.Nordlund@ki.se [Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm (Sweden); Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm (Sweden)

    2010-05-21

    Interactions are the foundation of life at the molecular level. In the plethora of activities in the cell, the evolution of enzyme specificity requires the balancing of appropriate substrate affinity with a negative selection, in order to minimize interactions with other potential substrates in the cell. To understand the structural basis for enzyme specificity, the comparison of structural and biochemical data between enzymes within pathways using similar substrates and effectors is valuable. Nucleotide metabolism is one of the largest metabolic pathways in the human cell and is of outstanding therapeutic importance since it activates and catabolises nucleoside based anti-proliferative drugs and serves as a direct target for anti-proliferative drugs. In recent years the structural coverage of the enzymes involved in human nucleotide metabolism has been dramatically improved and is approaching completion. An important factor has been the contribution from the Structural Genomics Consortium (SGC) at Karolinska Institutet, which recently has solved 33 novel structures of enzymes and enzyme domains in human nucleotide metabolism pathways and homologs thereof. In this review we will discuss some of the principles for substrate specificity of enzymes in human nucleotide metabolism illustrated by a selected set of enzyme families where a detailed understanding of the structural determinants for specificity is now emerging.

  11. Diabetes mellitus related bone metabolism and periodontal disease.

    Science.gov (United States)

    Wu, Ying-Ying; Xiao, E; Graves, Dana T

    2015-06-26

    Diabetes mellitus and periodontal disease are chronic diseases affecting a large number of populations worldwide. Changed bone metabolism is one of the important long-term complications associated with diabetes mellitus. Alveolar bone loss is one of the main outcomes of periodontitis, and diabetes is among the primary risk factors for periodontal disease. In this review, we summarise the adverse effects of diabetes on the periodontium in periodontitis subjects, focusing on alveolar bone loss. Bone remodelling begins with osteoclasts resorbing bone, followed by new bone formation by osteoblasts in the resorption lacunae. Therefore, we discuss the potential mechanism of diabetes-enhanced bone loss in relation to osteoblasts and osteoclasts.

  12. Diabetes mellitus related bone metabolism and periodontal disease

    Science.gov (United States)

    Wu, Ying-Ying; Xiao, E; Graves, Dana T

    2015-01-01

    Diabetes mellitus and periodontal disease are chronic diseases affecting a large number of populations worldwide. Changed bone metabolism is one of the important long-term complications associated with diabetes mellitus. Alveolar bone loss is one of the main outcomes of periodontitis, and diabetes is among the primary risk factors for periodontal disease. In this review, we summarise the adverse effects of diabetes on the periodontium in periodontitis subjects, focusing on alveolar bone loss. Bone remodelling begins with osteoclasts resorbing bone, followed by new bone formation by osteoblasts in the resorption lacunae. Therefore, we discuss the potential mechanism of diabetes-enhanced bone loss in relation to osteoblasts and osteoclasts. PMID:25857702

  13. Diabetes mellitus related bone metabolism and periodontal disease

    Institute of Scientific and Technical Information of China (English)

    Ying-Ying Wu; E Xiao; Dana T Graves

    2015-01-01

    Diabetes mellitus and periodontal disease are chronic diseases affecting a large number of populations worldwide. Changed bone metabolism is one of the important long-term complications associated with diabetes mellitus. Alveolar bone loss is one of the main outcomes of periodontitis, and diabetes is among the primary risk factors for periodontal disease. In this review, we summarise the adverse effects of diabetes on the periodontium in periodontitis subjects, focusing on alveolar bone loss. Bone remodelling begins with osteoclasts resorbing bone, followed by new bone formation by osteoblasts in the resorption lacunae. Therefore, we discuss the potential mechanism of diabetes-enhanced bone loss in relation to osteoblasts and osteoclasts.

  14. Metabolomics approach for discovering disease biomarkers and understanding metabolic pathway

    Directory of Open Access Journals (Sweden)

    Jeeyoun Jung

    2011-12-01

    Full Text Available Metabolomics, the multi-targeted analysis of endogenous metabolites from biological samples, can be efficiently applied to screen disease biomarkers and investigate pathophysiological processes. Metabolites change rapidly in response to physiological perturbations, making them the closest link to disease phenotypes. This study explored the role of metabolomics in gaining mechanistic insight into disease processes and in searching for novel biomarkers of human diseases

  15. Perfusion and metabolism imaging studies in Parkinson's disease

    DEFF Research Database (Denmark)

    Borghammer, Per

    2012-01-01

    Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are important tools in the evaluation of brain blood flow and glucose metabolism in Parkinson's disease (PD). However, conflicting results are reported in the literature depending on the type of imaging data...... analysis employed. The present review gives a comprehensive summary of the perfusion and metabolism literature in the field of PD research, including quantitative PET studies, normalized PET and SPECT studies, autoradiography studies in animal models of PD, and simulation studies of PD data...

  16. Absorption and metabolic fate of bioactive dietary benzoxazinoids in humans

    DEFF Research Database (Denmark)

    Adhikari, Khem B; Laursen, Bente B; Gregersen, Per L;

    2013-01-01

    Scope Benzoxazinoids, which are natural compounds recently identified in mature whole grain cereals and bakery products, have been suggested to have a range of pharmacological properties and health-protecting effects. There are no published reports concerned with the absorption and metabolism...... of bioactive benzoxazinoids in humans. Methods and results The absorption, metabolism, and excretion of ten different dietary benzoxazinoids were examined by LC-MS/MS by analyzing plasma and urine from 20 healthy human volunteers after daily intake of 143 μmol of total benzoxazinoids from rye bread and rye...... glycosides, the reduction of hydroxamic acid glycosides, glucuronidation, and sulfation were the main mechanisms of the absorption and metabolism of benzoxazinoids. Conclusion These results indicate that following ingestion in healthy humans, a range of unmetabolized bioactive dietary benzoxazinoids...

  17. Metabolic Dysfunction in Parkinson's Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism.

    Science.gov (United States)

    Anandhan, Annadurai; Jacome, Maria S; Lei, Shulei; Hernandez-Franco, Pablo; Pappa, Aglaia; Panayiotidis, Mihalis I; Powers, Robert; Franco, Rodrigo

    2017-07-01

    The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of protein inclusions (Lewy bodies) are the pathological hallmarks of Parkinson's disease (PD). PD is triggered by genetic alterations, environmental/occupational exposures and aging. However, the exact molecular mechanisms linking these PD risk factors to neuronal dysfunction are still unclear. Alterations in redox homeostasis and bioenergetics (energy failure) are thought to be central components of neurodegeneration that contribute to the impairment of important homeostatic processes in dopaminergic cells such as protein quality control mechanisms, neurotransmitter release/metabolism, axonal transport of vesicles and cell survival. Importantly, both bioenergetics and redox homeostasis are coupled to neuro-glial central carbon metabolism. We and others have recently established a link between the alterations in central carbon metabolism induced by PD risk factors, redox homeostasis and bioenergetics and their contribution to the survival/death of dopaminergic cells. In this review, we focus on the link between metabolic dysfunction, energy failure and redox imbalance in PD, making an emphasis in the contribution of central carbon (glucose) metabolism. The evidence summarized here strongly supports the consideration of PD as a disorder of cell metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Comparison of metabolism of sesamin and episesamin by drug-metabolizing enzymes in human liver.

    Science.gov (United States)

    Yasuda, Kaori; Ikushiro, Shinichi; Wakayama, Shuto; Itoh, Toshimasa; Yamamoto, Keiko; Kamakura, Masaki; Munetsuna, Eiji; Ohta, Miho; Sakaki, Toshiyuki

    2012-10-01

    Sesamin and episesamin are two epimeric lignans that are found in refined sesame oil. Commercially available sesamin supplements contain both sesamin and episesamin at an approximate 1:1 ratio. Our previous study clarified the sequential metabolism of sesamin by cytochrome P450 (P450) and UDP-glucuronosyltransferase in human liver. In addition, we revealed that sesamin caused a mechanism-based inhibition (MBI) of CYP2C9, the P450 enzyme responsible for sesamin monocatecholization. In the present study, we compared the metabolism and the MBI of episesamin with those of sesamin. Episesamin was first metabolized to the two epimers of monocatechol, S- and R-monocatechols in human liver microsomes. The P450 enzymes responsible for S- and R-monocatechol formation were CYP2C9 and CYP1A2, respectively. The contribution of CYP2C9 was much larger than that of CYP1A2 in sesamin metabolism, whereas the contribution of CYP2C9 was almost equal to that of CYP1A2 in episesamin metabolism. Docking of episesamin to the active site of CYP1A2 explained the stereoselectivity in CYP1A2-dependent episesamin monocatecholization. Similar to sesamin, the episesamin S- and R-monocatechols were further metabolized to dicatechol, glucuronide, and methylate metabolites in human liver; however, the contribution of each reaction was significantly different between sesamin and episesamin. The liver microsomes from CYP2C19 ultra-rapid metabolizers showed a significant amount of episesamin dicatechol. In this study, we have revealed significantly different metabolism by P450, UDP-glucuronosyltransferase, and catechol-O-methyltransferase for sesamin and episesamin, resulting in different biological effects.

  19. Metabolic heat production by human and animal populations in cities

    Science.gov (United States)

    Stewart, Iain D.; Kennedy, Chris A.

    2017-07-01

    Anthropogenic heating from building energy use, vehicle fuel consumption, and human metabolism is a key term in the urban energy budget equation. Heating from human metabolism, however, is often excluded from urban energy budgets because it is widely observed to be negligible. Few reports for low-latitude cities are available to support this observation, and no reports exist on the contribution of domestic animals to urban heat budgets. To provide a more comprehensive view of metabolic heating in cities, we quantified all terms of the anthropogenic heat budget at metropolitan scale for the world's 26 largest cities, using a top-down statistical approach. Results show that metabolic heat release from human populations in mid-latitude cities (e.g. London, Tokyo, New York) accounts for 4-8% of annual anthropogenic heating, compared to 10-45% in high-density tropical cities (e.g. Cairo, Dhaka, Kolkata). Heat release from animal populations amounts to world's most densely populated megacity—at 6.5 W m-2, surpassing heat production by electricity use in buildings (5.8 W m-2) and fuel combustion in vehicles (3.9 W m-2). These findings, along with recent output from global climate models, suggest that in the world's largest and most crowded cities, heat emissions from human metabolism alone can force measurable change in mean annual temperature at regional scale.

  20. Metabolomic applications to decipher gut microbial metabolic influence in health and disease

    Directory of Open Access Journals (Sweden)

    Francois-Pierre eMartin

    2012-04-01

    Full Text Available Dietary preferences and nutrients composition have been shown to influence human and gut microbial metabolism, which ultimately has specific effects on health and diseases’ risk. Increasingly, results from molecular biology and microbiology demonstrate the key role of the gut microbiota metabolic interface to the overall mammalian host’s health status. There is therefore raising interest in nutrition research to characterize the molecular foundations of the gut microbial mammalian cross-talk at both physiological and biochemical pathway levels. Tackling these challenges can be achieved through systems biology approaches, such as metabolomics, to underpin the highly complex metabolic exchanges between diverse biological compartments, including organs, systemic biofluids and microbial symbionts. By the development of specific biomarkers for prediction of health and disease, metabolomics is increasingly used in clinical applications as regard to disease aetiology, diagnostic stratification and potentially mechanism of action of therapeutical and nutraceutical solutions. Surprisingly, an increasing number of metabolomics investigations in pre-clinical and clinical studies based on proton nuclear magnetic resonance (1H NMR spectroscopy and mass spectrometry (MS provided compelling evidence that system wide and organ-specific biochemical processes are under the influence of gut microbial metabolism. This review aims at describing recent applications of metabolomics in clinical fields where main objective is to discern the biochemical mechanisms under the influence of the gut microbiota, with insight into gastrointestinal health and diseases diagnostics and improvement of homeostasis metabolic regulation.

  1. Morphine metabolism in human skin microsomes.

    Science.gov (United States)

    Heilmann, S; Küchler, S; Schäfer-Korting, M

    2012-01-01

    For patients with severe skin wounds, topically applied morphine is an option to induce efficient analgesia due to the presence of opioid receptors in the skin. However, for topical administration it is important to know whether the substance is biotransformed in the skin as this can eventually reduce the concentration of the active agent considerably. We use skin microsomes to elucidate the impact of skin metabolism on the activity of topically applied morphine. We are able to demonstrate that morphine is only glucuronidated in traces, indicating that the biotransformation in the skin can be neglected when morphine is applied topically. Hence, there is no need to take biotransformation into account when setting up the treatment regimen.

  2. In silico prediction of xenobiotic metabolism in humans

    Energy Technology Data Exchange (ETDEWEB)

    Mu, Fangping [Los Alamos National Laboratory

    2009-01-01

    Xenobiotic metabolism in humans is catalyzed by a few enzymes with broad substrate specificities, which provide the overall broad chemical specificity for nearly all xenobiotics that humans encounter. Xenobiotic metabolism are classified into functional group biotransformations. Based on bona fide reactions and negative examples for each reaction class, support vector machine (SVM) classifiers are built. The input to SVM is a set of atomic and molecular features to define the electrostatic, steric, energetic, geometrical and topological environment of the atoms in the reaction center under the molecule. Results show that the overall sensitivity and specificity of classifiers is around 87%.

  3. multicopper oxidases important for human iron metabolism

    Directory of Open Access Journals (Sweden)

    Diana Wierzbicka

    2014-01-01

    Full Text Available Multi-copper oxidases are a group of proteins which demonstrate enzymatic activity and are capable of oxidizing their substrates with the concomitant reduction of dioxygen to two water molecules. For some multi-copper oxidases there has been demonstrated ferroxidase activity which is related to their specific structure characterized by the presence of copper centres and iron-binding sites. Three multi-copper oxidases have been included in this group: ceruloplasmin, hephaestin and zyklopen. Multi copper oxidases which are expressed in different tissues are capable of oxidizing a wide spectrum of substrates. Multi-copper oxidases are capable of oxidizing a wide spectrum of substrates. Ceruloplasmin exhibits antioxidant activity as well as being involved in many other biological processes. The observations of phenotypic effects of absence or low expression of multi-copper ferroxidase-coding genes suggest that the main role of these proteins is taking part in iron metabolism. The main role of ceruloplasmin in iron turnover is oxidizing Fe2+ into Fe3+, a process which is essential for iron binding to transferrin (the main iron-transporting protein, as well as to ferritin (the main iron-storage protein. The function of hephaestin as ferroxidase is essential for iron binding to apotransferrin in the lamina propria of the intestinal mucosa, a process that is important for further transport of iron to the liver by the portal vein. Available data indicate that zyklopen is responsible for the placental iron transport. The presence of three multi-copper oxidases with ferroxidase activity emphasizes the significance of oxidation for iron metabolism. The distribution of multi-copper ferroxidases in many tissues ensures the proper iron turnover in the body as well as preventing toxic effects related to the presence of Fe2+ ions. These ions contribute to generation of free radicals, including the highly reactive hydroxyl radical, through the Fenton and Haber

  4. The Endocannabinoid System: Pivotal Orchestrator of Obesity and Metabolic Disease.

    Science.gov (United States)

    Mazier, Wilfrid; Saucisse, Nicolas; Gatta-Cherifi, Blandine; Cota, Daniela

    2015-10-01

    The endocannabinoid system (ECS) functions to adjust behavior and metabolism according to environmental changes in food availability. Its actions range from the regulation of sensory responses to the development of preference for the consumption of calorically-rich food and control of its metabolic handling. ECS activity is beneficial when access to food is scarce or unpredictable. However, when food is plentiful, the ECS favors obesity and metabolic disease. We review recent advances in understanding the roles of the ECS in energy balance, and discuss newly identified mechanisms of action that, after the withdrawal of first generation cannabinoid type 1 (CB1) receptor antagonists for the treatment of obesity, have made the ECS once again an attractive target for therapy.

  5. Enantioselective Metabolism of Flufiprole in Rat and Human Liver Microsomes.

    Science.gov (United States)

    Lin, Chunmian; Miao, Yelong; Qian, Mingrong; Wang, Qiang; Zhang, Hu

    2016-03-23

    The enantioselective metabolism of flufiprole in rat and human liver microsomes in vitro was investigated in this study. The separation and determination were performed using a liquid chromatography system equipped with a triple-quadrupole mass spectrometer and a Lux Cellulose-2 chiral column. The enantioselective metabolism of rac-flufiprole was dramatically different in rat and human liver microsomes in the presence of the β-nicotinamide adenine dinucleotide phosphate regenerating system. The half-lives (t1/2) of flufiprole in rat and human liver microsomes were 7.22 and 21.00 min, respectively, for R-(+)-flufiprole, whereas the values were 11.75 and 17.75 min, respectively, for S-(-)-flufiprole. In addition, the Vmax of R-(+)-flufiprole was about 3-fold that of S-(-)-flufiprole in rat liver microsomes, whereas its value in the case of S-(-)-flufiprole was about 2-fold that of R-(+)-flufiprole in human liver microsomes. The CLint of rac-flufiprole also showed opposite enantioselectivy in rat and human liver microsomes. The different compositions and contents of metabolizing enzyme in the two liver microsomes might be the reasons for the difference in the metabolic behavior of the two enantiomers.

  6. Gastrointestinal metabolization of human milk oligosaccharides

    NARCIS (Netherlands)

    Albrecht, S.A.; Heuvel, van den E.G.H.M.; Gruppen, H.; Schols, H.A.

    2013-01-01

    Breast feeding has a great impact on the growth of infants both physically and psychologically. Human breast milk is beneficial to infant health because it contains the necessary macro- and micro-nutrients for tissue accretion, repair and behavioural developments. The production of milk is a complex

  7. Metabolic Syndrome and Periodontal Disease Progression in Men.

    Science.gov (United States)

    Kaye, E K; Chen, N; Cabral, H J; Vokonas, P; Garcia, R I

    2016-07-01

    Metabolic syndrome, a cluster of 3 or more risk factors for cardiovascular disease, is associated with periodontal disease, but few studies have been prospective in design. This study's aim was to determine whether metabolic syndrome predicts tooth loss and worsening of periodontal disease in a cohort of 760 men in the Department of Veterans Affairs Dental Longitudinal Study and Normative Aging Study who were followed up to 33 y from 1981 to 2013. Systolic and diastolic blood pressures were measured with a standard mercury sphygmomanometer. Waist circumference was measured in units of 0.1 cm following a normal expiration. Fasting blood samples were measured in duplicate for glucose, triglyceride, and high-density lipoprotein. Calibrated periodontists served as dental examiners. Periodontal outcome events on each tooth were defined as progression to predefined threshold levels of probing pocket depth (≥5 mm), clinical attachment loss (≥5 mm), mobility (≥0.5 mm), and alveolar bone loss (≥40% of the distance from the cementoenamel junction to the root apex, on radiographs). Hazards ratios (95% confidence intervals) of tooth loss or a periodontitis event were estimated from tooth-level extended Cox proportional hazards regression models that accounted for clustering of teeth within individuals and used time-dependent status of metabolic syndrome. Covariates included age, education, smoking status, plaque level, and initial level of the appropriate periodontal disease measure. Metabolic syndrome as defined by the International Diabetes Federation increased the hazards of tooth loss (1.39; 1.08 to 1.79), pocket depth ≥5 mm (1.37; 1.14 to 1.65), clinical attachment loss ≥5 mm (1.19; 1.00 to 1.41), alveolar bone loss ≥40% (1.25; 1.00 to 1.56), and tooth mobility ≥0.5 mm (1.43; 1.07 to 1.89). The number of positive metabolic syndrome conditions was also associated with each of these outcomes. These findings suggest that the metabolic disturbances that

  8. Influence of metabolic syndrome on upper gastrointestinal disease.

    Science.gov (United States)

    Sogabe, Masahiro; Okahisa, Toshiya; Kimura, Tetsuo; Okamoto, Koichi; Miyamoto, Hiroshi; Muguruma, Naoki; Takayama, Tetsuji

    2016-08-01

    A recent increase in the rate of obesity as a result of insufficient physical exercise and excess food consumption has been seen in both developed and developing countries throughout the world. Additionally, the recent increased number of obese individuals with lifestyle-related diseases associated with abnormalities in glucose metabolism, dyslipidemia, and hypertension, defined as metabolic syndrome (MS), has been problematic. Although MS has been highlighted as a risk factor for ischemic heart disease and arteriosclerotic diseases, it was also recently shown to be associated with digestive system disorders, including upper gastrointestinal diseases. Unlike high body weight and high body mass index, abdominal obesity with visceral fat accumulation is implicated in the onset of various digestive system diseases because excessive visceral fat accumulation may cause an increase in intra-abdominal pressure, inducing the release of various bioactive substances, known as adipocytokines, including tumor necrosis factor-α, interleukin-6, resistin, leptin, and adiponectin. This review article focuses on upper gastrointestinal disorders and their association with MS, including obesity, visceral fat accumulation, and the major upper gastrointestinal diseases.

  9. Apolipoprotein M in lipid metabolism and cardiometabolic diseases

    DEFF Research Database (Denmark)

    Borup, Anna; Christensen, Pernille Meyer; Nielsen, Lars B.

    2015-01-01

    PURPOSE: This review will address recent findings on apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) in lipid metabolism and inflammatory diseases. RECENT FINDINGS: ApoM's likely role(s) in health and disease has become more diverse after the discovery that apoM functions...... as a chaperone for S1P. Hence, apoM has recently been implicated in lipid metabolism, diabetes and rheumatoid arthritis through in-vivo, in-vitro and genetic association studies. It remains to be established to which degree such associations with apoM can be attributed to its ability to bind S1P. SUMMARY......: The apoM/S1P axis and its implications in atherosclerosis and lipid metabolism have been thoroughly studied. Owing to the discovery of the apoM/S1P axis, the scope of apoM research has broadened. ApoM and S1P have been implicated in lipid metabolism, that is by modulating HDL particles. Also...

  10. Abnormal erythrocyte metabolism in hepatic disease: effect of NADP repletion.

    Science.gov (United States)

    Smith, J R; Kay, N E; Gottlieb, A J; Oski, F A

    1979-01-01

    Erythrocytes from ten patients with severe liver disease displayed low methylene blue-stimulated hexose monophosphate (HMP) shunt activity and glucose recycling despite elevated total glucose consumption when compared to controls. Heinz body formation was increased and reduced glutathione concentration significantly decreased. After hemolysis, no differences in methylene-blue estimulated HMP shunt activity or glucose recycling could be demonstrated between patients and controls. The addition of 2- and 4-mM NADP to the hemolysates produced significantly greater HMP shunt activity and glucose recycling in the patients' hemolysates. The addition of NADPH to the incubation mixture produced no significant stimulation of either HMP shunt activity or glucose recycling, unless methylene blue was also added. Omission of NAD or phosphate from the incubation mixture produced no change in shunt metabolism. The absence of supplemental ATP resulted in extremely low shunt metabolism and refractoriness to NADP stimulation in both patients and controls. In the absence of additional magnesium, a reduction of shunt metabolism was noted. These data suggest that the defect in stimulated shunt metabolism in the intact erythrocytes of patients with hepatic disease does not result from an absolute enzyme deficiency, but rather from an unavailability of NADP or other cofactor.

  11. Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease

    Science.gov (United States)

    Azhar, Salman

    2011-01-01

    Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARα, PPARδ/β and PPARγ are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARα (fibrates) and PPARγ (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones. PMID:20932114

  12. Metabolism of fatty acids and lipid hydroperoxides in human body monitoring with Fourier transform Infrared Spectroscopy

    Directory of Open Access Journals (Sweden)

    Zhang Qin-Zeng

    2009-07-01

    Full Text Available Abstract Background The metabolism of dietary fatty acids in human has been measured so far using human blood cells and stable-isotope labeled fatty acids, however, no direct data was available for human peripheral tissues and other major organs. To realize the role of dietary fatty acids in human health and diseases, it would be eager to develop convenient and suitable method to monitor fatty acid metabolism in human. Results We have developed the measurement system in situ for human lip surface lipids using the Fourier transform infrared spectroscopy (FTIR – attenuated total reflection (ATR detection system with special adaptor to monitor metabolic changes of lipids in human body. As human lip surface lipids may not be much affected by skin sebum constituents and may be affected directly by the lipid constituents of diet, we could detect changes of FTIR-ATR spectra, especially at 3005~3015 cm-1, of lip surface polyunsaturated fatty acids in a duration time-dependent manner after intake of the docosahexaenoic acid (DHA-containing triglyceride diet. The ingested DHA appeared on the lip surface and was detected by FTIR-ATR directly and non-invasively. It was found that the metabolic rates of DHA for male volunteer subjects with age 60s were much lower than those with age 20s. Lipid hydroperoxides were found in lip lipids which were extracted from the lip surface using a mixture of ethanol/ethylpropionate/iso-octane solvents, and were the highest in the content just before noon. The changes of lipid hydroperoxides were detected also in situ with FTIR-ATR at 968 cm-1. Conclusion The measurements of lip surface lipids with FTIR-ATR technique may advance the investigation of human lipid metabolism in situ non-invasively.

  13. Metabolic syndrome--psycho neuropathogenesis and human brain evolution.

    Science.gov (United States)

    Perumal, Madhusoothanan Bhagavathi

    2011-01-01

    Metabolic syndrome (MS) is a major risk factor for coronary artery disease. Heightened hypothalamo-pituitary-adrenal axis activity is associated with pathogenesis of MS. Life style, food habits and physical activity also play critical role in the pathogenesis of MS. However, the precise neurophysiology behind chronic stress leading on to such effects is unknown. Review of recent animal and human studies have shown the subtle differences in morphological changes associated with chronic stress between medial prefrontal cortex and amygdaloid complex. The loss of dendritic spines in pyramidal neurons of medial prefrontal cortex, dendritic hypertrophy in basolateral amygdala and dendritic loss in central nucleus of amygdala causes increased basal output from amygdaloid complex to HPA axis and other targets whose networks are evolutionarily well conserved. The increased HPA axis activity, elevated blood pressure and appetite for high calorie diet leads to MS. The evolution of isocortex in primates and associated regression in size of limbic structures predisposed to increased synaptic noise in amygdaloid complex which in turn cause heighetened output from amygdala during chronic stress. Copyright © 2010 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  14. Hepatic metabolism of toluene after gastrointestinal uptake in humans

    DEFF Research Database (Denmark)

    Bælum, Jesper; Mølhave, Lars; Honoré Hansen, S

    1993-01-01

    The metabolism of toluene and the influence of small doses of ethanol were measured in eight male volunteers after gastrointestinal uptake, the toluene concentration in alveolar air and the urinary excretion of hippuric acid and ortho-cresol being used as the measures of metabolism. During toluene...... exposure to 2 mg.min-1 for 3 h the alveolar toluene concentration was 0.07 (range 0-0.11) mg.m-3; exposure to 6 mg.min-1 for 30 min increased the alveolar concentration to 0.9 (range 0.03-2.6) mg.m-3. Ingestion of 0.08, 0.16, and 0.32 g of ethanol per kilogram of body weight during toluene exposure of 2 mg...... doses of ethanol inhibit toluene metabolism, and the procedure is sensitive enough to measure metabolic interactions between solvents and other xenobiotics in humans....

  15. Metabolism as a tool for understanding human brain evolution: lipid energy metabolism as an example.

    Science.gov (United States)

    Wang, Shu Pei; Yang, Hao; Wu, Jiang Wei; Gauthier, Nicolas; Fukao, Toshiyuki; Mitchell, Grant A

    2014-12-01

    Genes and the environment both influence the metabolic processes that determine fitness. To illustrate the importance of metabolism for human brain evolution and health, we use the example of lipid energy metabolism, i.e. the use of fat (lipid) to produce energy and the advantages that this metabolic pathway provides for the brain during environmental energy shortage. We briefly describe some features of metabolism in ancestral organisms, which provided a molecular toolkit for later development. In modern humans, lipid energy metabolism is a regulated multi-organ pathway that links triglycerides in fat tissue to the mitochondria of many tissues including the brain. Three important control points are each suppressed by insulin. (1) Lipid reserves in adipose tissue are released by lipolysis during fasting and stress, producing fatty acids (FAs) which circulate in the blood and are taken up by cells. (2) FA oxidation. Mitochondrial entry is controlled by carnitine palmitoyl transferase 1 (CPT1). Inside the mitochondria, FAs undergo beta oxidation and energy production in the Krebs cycle and respiratory chain. (3) In liver mitochondria, the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) pathway produces ketone bodies for the brain and other organs. Unlike most tissues, the brain does not capture and metabolize circulating FAs for energy production. However, the brain can use ketone bodies for energy. We discuss two examples of genetic metabolic traits that may be advantageous under most conditions but deleterious in others. (1) A CPT1A variant prevalent in Inuit people may allow increased FA oxidation under nonfasting conditions but also predispose to hypoglycemic episodes. (2) The thrifty genotype theory, which holds that energy expenditure is efficient so as to maximize energy stores, predicts that these adaptations may enhance survival in periods of famine but predispose to obesity in modern dietary environments. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Anthropometric parameters--predictive factors for cardio-metabolic diseases.

    Science.gov (United States)

    Mihalache, Laura; Graur, Lidia Iuliana; Popescu, Dana Stefana; Niţă, Otilia; Graur, Mariana

    2012-01-01

    The aim of this study was to evaluate comparatively the predictive power of body mass index (BMI) and waist circumference (WC), two anthropometric parameters used in daily practice, for detecting cardio-metabolic diseases, in a rural community in north-east Romania. We evaluated 3248 persons, aged 19 or over, for whom we collected the following data: medical history, anthropometric parameters, blood pressure value and biochemical parameters. Both WC and BMI help correctly determine the presence of arterial hypertension, diabetes and dislipidemia. However, the cut-off value of each of these parameters differs for each pathology. The predictive value of WC for different cardio-metabolic diseases is maintained even at normal or borderline overweight values of BMI.

  17. [Gene transfer as treatment for metabolic inherited liver diseases

    Science.gov (United States)

    Godoy, J L

    2000-01-01

    OBJECTIVE: To study gene transfer looking for its future clinical application in the treatment of metabolic inherited liver diseases. METHODS: Bibliographic review about the subject. RESULTS AND CONCLUSIONS: Gene transfer into the liver would be an alternative to liver transplantation to treat some inherited metabolic diseases. Various vectors have been employed for gene transfer, including retrovirus vectors, whose integration into the chromosomal DNA would allow stable long term expression of the transgene. The integration of retrovirus vectors into the genoma of the target cell is only possible during mitosis. Therefore, these vectors must be delivered during hepatic regeneration induced by partial hepatectomy, for example. Another obstacle to be overcome is the extra hepatic dissemination of retrovirus, in particular to the germinals cells, due to the risk of changing the genetical heritage of the progeniture.

  18. Lipoprotein Metabolism, Dyslipidemia and Nonalcoholic Fatty Liver Disease

    Science.gov (United States)

    Cohen, David E.; Fisher, Edward A.

    2014-01-01

    Cardiovascular disease represents the most common cause of death in patients with non-alcoholic fatty liver disease (NAFLD). NAFLD patients exhibit an atherogenic dyslipidemia that is characterized by an increased plasma concentration of triglycerides, reduced concentration of high density lipoprotein (HDL) cholesterol, and low density lipoprotein (LDL) particles that are smaller and more dense than normal. The pathogenesis of NAFLD-associated atherogenic dyslipidemia is multifaceted, but many aspects are attributable to manifestations of insulin resistance. Here we review the structure, function and metabolism of lipoproteins, which are macromolecular particles of lipids and proteins that transport otherwise insoluble triglyceride and cholesterol molecules within the plasma. We provide a current explanation of the metabolic perturbations that are observed in the setting of insulin resistance. An improved understanding of the pathophysiology of atherogenic dyslipidemia would be expected to guide therapies aimed at reducing morbidity and mortality in NAFLD patients. PMID:24222095

  19. Metabolic costs and evolutionary implications of human brain development.

    Science.gov (United States)

    Kuzawa, Christopher W; Chugani, Harry T; Grossman, Lawrence I; Lipovich, Leonard; Muzik, Otto; Hof, Patrick R; Wildman, Derek E; Sherwood, Chet C; Leonard, William R; Lange, Nicholas

    2014-09-09

    The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.

  20. Correlation between blood adenosine metabolism and sleep in humans.

    Science.gov (United States)

    Díaz-Muñoz, M; Hernández-Muñoz, R; Suárez, J; Vidrio, S; Yááñez, L; Aguilar-Roblero, R; Rosenthal, L; Villalobos, L; Fernández-Cancino, F; Drucker-Colín, R; Chagoya De Sanchez, V

    1999-01-01

    Blood adenosine metabolism, including metabolites and metabolizing enzymes, was studied during the sleep period in human volunteers. Searching for significant correlations among biochemical parameters found: adenosine with state 1 of slow-wave sleep (SWS); activity of 5'-nucleotidase with state 2 of SWS; inosine and AMP with state 3-4 of SWS; and activity of 5'-nucleotidase and lactate with REM sleep. The correlations were detected in all of the subjects that presented normal hypnograms, but not in those who had fragmented sleep the night of the experiment. The data demonstrate that it is possible to obtain information of complex brain operations such as sleep by measuring biochemical parameters in blood. The results strengthen the notion of a role played by adenosine, its metabolites and metabolizing enzymes, during each of the stages that constitute the sleep process in humans.

  1. IL-6 selectively stimulates fat metabolism in human skeletal muscle

    DEFF Research Database (Denmark)

    Wolsk, Emil; Mygind, Helene; Grøndahl, Thomas S

    2010-01-01

    Interleukin (IL)-6 is chronically elevated in type 2 diabetes but also during exercise. However, the exact metabolic role, and hence the physiological significance, has not been elucidated. The objective of this study was to investigate the in vivo effect of recombinant human (rh) IL-6 on human fat...... and glucose metabolism and signaling of both adipose tissue and skeletal muscle. Eight healthy postabsorptive males were infused with either rhIL-6 or saline for 4 h, eliciting IL-6 levels of ~40 and ~1 pg/ml, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism was assessed...... in systemic lipolysis. Adipose tissue lipolysis and fatty acid kinetics were unchanged with rhIL-6 compared with saline infusion. Conversely, rhIL-6 infusion caused an increase in skeletal muscle unidirectional fatty acid and glycerol release, indicative of an increase in lipolysis. The increased lipolysis...

  2. Metabolic syndrome in rheumatic diseases: epidemiology, pathophysiology, and clinical implications

    OpenAIRE

    Sidiropoulos, Prodromos I; Karvounaris, Stylianos A; Boumpas, Dimitrios T.

    2008-01-01

    Subjects with metabolic syndrome–a constellation of cardiovascular risk factors of which central obesity and insulin resistance are the most characteristic–are at increased risk for developing diabetes mellitus and cardiovascular disease. In these subjects, abdominal adipose tissue is a source of inflammatory cytokines such as tumor necrosis factor-alpha, known to promote insulin resistance. The presence of inflammatory cytokines together with the well-documented increased risk for cardiovasc...

  3. Skeletal muscle metabolism during prolonged exercise in Pompe disease

    Directory of Open Access Journals (Sweden)

    Nicolai Preisler

    2017-07-01

    Full Text Available Objective: Pompe disease (glycogenosis type II is caused by lysosomal alpha-glucosidase deficiency, which leads to a block in intra-lysosomal glycogen breakdown. In spite of enzyme replacement therapy, Pompe disease continues to be a progressive metabolic myopathy. Considering the health benefits of exercise, it is important in Pompe disease to acquire more information about muscle substrate use during exercise. Methods: Seven adults with Pompe disease were matched to a healthy control group (1:1. We determined (1 peak oxidative capacity (VO2peak and (2 carbohydrate and fatty acid metabolism during submaximal exercise (33 W for 1 h, using cycle-ergometer exercise, indirect calorimetry and stable isotopes. Results: In the patients, VO2peak was less than half of average control values; mean difference −1659 mL/min (CI: −2450 to −867, P = 0.001. However, the respiratory exchange ratio increased to >1.0 and lactate levels rose 5-fold in the patients, indicating significant glycolytic flux. In line with this, during submaximal exercise, the rates of oxidation (ROX of carbohydrates and palmitate were similar between patients and controls (mean difference 0.226 g/min (CI: 0.611 to −0.078, P = 0.318 and mean difference 0.016 μmol/kg/min (CI: 1.287 to −1.255, P = 0.710, respectively. Conclusion: Reflecting muscle weakness and wasting, Pompe disease is associated with markedly reduced maximal exercise capacity. However, glycogenolysis is not impaired in exercise. Unlike in other metabolic myopathies, skeletal muscle substrate use during exercise is normal in Pompe disease rendering exercise less complicated for e.g. medical or recreational purposes.

  4. Metabolism and pharmacokinetics of indacaterol in humans.

    Science.gov (United States)

    Kagan, Mark; Dain, Jeremy; Peng, Lana; Reynolds, Christine

    2012-09-01

    The metabolism, pharmacokinetics, and excretion of [(14)C]indacaterol were investigated in healthy male subjects. Although indacaterol is administered to patients via inhalation, the dose in this study was administered orally. This was done to avoid the complications and concerns associated with the administration of a radiolabeled compound via the inhalation route. The submilligram doses administered in this study made metabolite identification and structural elucidation by mass spectrometry especially challenging. In serum, the mean t(max), C(max), and AUC(0-last) values were 1.75 h, 0.47 ng/ml, and 1.81 ng · h/ml for indacaterol and 2.5 h, 1.4 ngEq/ml, and 27.2 ngEq · h/ml for total radioactivity. Unmodified indacaterol was the most abundant drug-related compound in the serum, contributing 30% to the total radioactivity in the AUC(0-24h) pools, whereas monohydroxylated indacaterol (P26.9), the glucuronide conjugate of P26.9 (P19), and the 8-O-glucuronide conjugate of indacaterol (P37) were the most abundant metabolites, with each contributing 4 to 13%. In addition, the N-glucuronide (2-amino) conjugate (P37.7) and two metabolites (P38.2 and P39) that resulted from the cleavage about the aminoethanol group linking the hydroxyquinolinone and diethylindane moieties had a combined contribution of 12.5%. For all four subjects in the study, ≥90% of the radioactivity dose was recovered in the excreta (85% in feces and 10% in urine, mean values). In feces, unmodified indacaterol and metabolite P26.9 were the most abundant drug-related compounds (54 and 17% of the dose, respectively). In urine, unmodified indacaterol accounted for ∼0.3% of the dose, with no single metabolite accounting for >1.3%.

  5. Richness of human gut microbiome correlates with metabolic markers

    DEFF Research Database (Denmark)

    Le Chatelier, Emmanuelle; Nielsen, Trine; Qin, Junjie

    2013-01-01

    We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus...

  6. Aflatoxin B1 transfer and metabolism in human placenta.

    Science.gov (United States)

    Partanen, Heidi A; El-Nezami, Hani S; Leppänen, Jukka M; Myllynen, Päivi K; Woodhouse, Heather J; Vähäkangas, Kirsi H

    2010-01-01

    Aflatoxin B1 (AFB1), a common dietary contaminant, is a major risk factor of hepatocellular carcinoma (HCC). Early onset of HCC in some countries in Africa and South-East Asia indicates the importance of early life exposure. Placenta is the primary route for various compounds, both nutrients and toxins, from the mother to the fetal circulation. Furthermore, placenta contains enzymes for xenobiotic metabolism. AFB1, AFB1-metabolites, and AFB1-albumin adducts have been detected in cord blood of babies after maternal exposure during pregnancy. However, the role that the placenta plays in the transfer and metabolism of AFB1 is not clear. In this study, placental transfer and metabolism of AFB1 were investigated in human placental perfusions and in in vitro studies. Eight human placentas were perfused with 0.5 or 5microM AFB1 for 2-4 h. In vitro incubations with placental microsomal and cytosolic proteins from eight additional placentas were also conducted. Our results from placental perfusions provide the first direct evidence of the actual transfer of AFB1 and its metabolism to aflatoxicol (AFL) by human placenta. In vitro incubations with placental cytosolic fraction confirmed the capacity of human placenta to form AFL. AFL was the only metabolite detected in both perfusions and in vitro incubations. Since AFL is less mutagenic, but putatively as carcinogenic as AFB1, the formation of AFL may not protect the fetus from the toxicity of AFB1.

  7. Diet-microbiota interactions as moderators of human metabolism

    DEFF Research Database (Denmark)

    Sonnenburg, Justin L; Bäckhed, Gert Fredrik

    2016-01-01

    are coming to light through a powerful combination of translation-focused animal models and studies in humans. A body of knowledge is accumulating that points to the gut microbiota as a mediator of dietary impact on the host metabolic status. Efforts are focusing on the establishment of causal relationships...

  8. Evolutionary Medicine: The Ongoing Evolution of Human Physiology and Metabolism.

    Science.gov (United States)

    Rühli, Frank; van Schaik, Katherine; Henneberg, Maciej

    2016-11-01

    The field of evolutionary medicine uses evolutionary principles to understand changes in human anatomy and physiology that have occurred over time in response to environmental changes. Through this evolutionary-based approach, we can understand disease as a consequence of anatomical and physiological "trade-offs" that develop to facilitate survival and reproduction. We demonstrate how diachronic study of human anatomy and physiology is fundamental for an increased understanding of human health and disease.

  9. Insights into metabolic disease from studying genetics in isolated populations

    DEFF Research Database (Denmark)

    Zeggini, Eleftheria; Gloyn, Anna L; Hansen, Torben

    2016-01-01

    for diabetes and metabolic disease, drawing on specific examples from populations in Greece and Greenland. This review summarises a presentation given at the 'Exciting news in genetics of diabetes' symposium at the 2015 annual meeting of the EASD, with topics presented by Eleftheria Zeggini and Torben Hansen...... variation on disease risk. Current efforts are now focused on extending this to genetic variants in the rare and low-frequency spectrum by capitalising on next-generation sequencing technologies. This review discusses the important contributions that studies in isolated populations are making to this effort...

  10. The heart-liver metabolic axis: defective communication exacerbates disease.

    Science.gov (United States)

    Baskin, Kedryn K; Bookout, Angie L; Olson, Eric N

    2014-04-01

    The heart has been recognized as an endocrine organ for over 30 years (de Bold, 2011); however, little is known about how the heart communicates with other organs in the body, and even less is known about this process in the diseased heart. In this issue of EMBO Molecular Medicine, Magida and Leinwand (2014) introduce the concept that a primary genetic defect in the heart results in aberrant hepatic lipid metabolism, which consequently exacerbates hypertrophic cardiomyopathy (HCM). This study provides evidence in support of the hypothesis that crosstalk occurs between the heart and liver, and that this becomes disrupted in the diseased state.

  11. Integrative neurobiology of metabolic diseases, neuroinflammation, and neurodegeneration

    Directory of Open Access Journals (Sweden)

    Gertjan eVan Dijk

    2015-05-01

    Full Text Available Alzheimer’s disease (AD is a complex, multifactorial disease with a number of leading mechanisms, including neuroinflammation, processing of amyloid precursor protein (APP to amyloid β peptide, tau protein hyperphosphorylation, relocalization and deposition. These mechanisms are propagated by obesity, the metabolic syndrome and type-2 diabetes mellitus. Stress, sedentariness, dietary overconsumption of saturated fat and refined sugars, and circadian derangements/disturbed sleep contribute to obesity and related metabolic diseases, but also accelerate age-related damage and senescence that all feed the risk of developing AD too. The complex and interacting mechanisms are not yet completely understood and will require further analysis. Instead of investigating AD as a mono- or oligocausal disease we should address the disease by understanding the multiple underlying mechanisms and how these interact. Future research therefore might concentrate on integrating these by systems biology approaches, but also to regard them from an evolutionary medicine point of view. The current review addresses several of these interacting mechanisms in animal models and compares them with clinical data giving an overview about our current knowledge and puts them into an integrated framework.

  12. The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health

    Directory of Open Access Journals (Sweden)

    Henrieta Škovierová

    2016-10-01

    Full Text Available Homocysteine (Hcy is a sulfur-containing non-proteinogenic amino acid derived in methionine metabolism. The increased level of Hcy in plasma, hyperhomocysteinemia, is considered to be an independent risk factor for cardio and cerebrovascular diseases. However, it is still not clear if Hcy is a marker or a causative agent of diseases. More and more research data suggest that Hcy is an important indicator for overall health status. This review represents the current understanding of molecular mechanism of Hcy metabolism and its link to hyperhomocysteinemia-related pathologies in humans. The aberrant Hcy metabolism could lead to the redox imbalance and oxidative stress resulting in elevated protein, nucleic acid and carbohydrate oxidation and lipoperoxidation, products known to be involved in cytotoxicity. Additionally, we examine the role of Hcy in thiolation of proteins, which results in their molecular and functional modifications. We also highlight the relationship between the imbalance in Hcy metabolism and pathogenesis of diseases, such as cardiovascular diseases, neurological and psychiatric disorders, chronic kidney disease, bone tissue damages, gastrointestinal disorders, cancer, and congenital defects.

  13. Targeting Adipose Tissue Lipid Metabolism to Improve Glucose Metabolism in Cardiometabolic Disease

    Directory of Open Access Journals (Sweden)

    Johan W.E. Jocken

    2014-10-01

    Full Text Available With Type 2 diabetes mellitus and cardiovascular disease prevalence on the rise, there is a growing need for improved strategies to prevent or treat obesity and insulin resistance, both of which are major risk factors for these chronic diseases. Impairments in adipose tissue lipid metabolism seem to play a critical role in these disorders. In the classical picture of intracellular lipid breakdown, cytosolic lipolysis was proposed as the sole mechanism for triacylglycerol hydrolysis in adipocytes. Recent evidence suggests involvement of several hormones, membrane receptors, and intracellular signalling cascades, which has added complexity to the regulation of cytosolic lipolysis. Interestingly, a specific form of autophagy, called lipophagy, has been implicated as alternative lipolytic pathway. Defective regulation of cytosolic lipolysis and lipophagy might have substantial effects on lipid metabolism, thereby contributing to adipose tissue dysfunction, insulin resistance, and related cardiometabolic (cMet diseases. This review will discuss recent advances in our understanding of classical lipolysis and lipophagy in adipocyte lipid metabolism under normal and pathological conditions. Furthermore, the question of whether modulation of adipocyte lipolysis and lipophagy might be a potential therapeutic target to combat cMet disorders will be addressed.

  14. Metabolite profiling identifies pathways associated with metabolic risk in humans.

    Science.gov (United States)

    Cheng, Susan; Rhee, Eugene P; Larson, Martin G; Lewis, Gregory D; McCabe, Elizabeth L; Shen, Dongxiao; Palma, Melinda J; Roberts, Lee D; Dejam, Andre; Souza, Amanda L; Deik, Amy A; Magnusson, Martin; Fox, Caroline S; O'Donnell, Christopher J; Vasan, Ramachandran S; Melander, Olle; Clish, Clary B; Gerszten, Robert E; Wang, Thomas J

    2012-05-08

    Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood. To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmö Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients, -0.04 to -0.22 per 1-SD change in log-glutamine; Prisk of incident diabetes mellitus in FHS (odds ratio, 0.79; adjusted P=0.03) but not in MDC. In experimental models, administration of glutamine in mice led to both increased glucose tolerance (P=0.01) and decreased blood pressure (Pprofiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice.

  15. Inhibition of fatty acid metabolism reduces human myeloma cells proliferation.

    Directory of Open Access Journals (Sweden)

    José Manuel Tirado-Vélez

    Full Text Available Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40-70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma.

  16. Application of chimeric mice with humanized liver for study of human-specific drug metabolism.

    Science.gov (United States)

    Bateman, Thomas J; Reddy, Vijay G B; Kakuni, Masakazu; Morikawa, Yoshio; Kumar, Sanjeev

    2014-06-01

    Human-specific or disproportionately abundant human metabolites of drug candidates that are not adequately formed and qualified in preclinical safety assessment species pose an important drug development challenge. Furthermore, the overall metabolic profile of drug candidates in humans is an important determinant of their drug-drug interaction susceptibility. These risks can be effectively assessed and/or mitigated if human metabolic profile of the drug candidate could reliably be determined in early development. However, currently available in vitro human models (e.g., liver microsomes, hepatocytes) are often inadequate in this regard. Furthermore, the conduct of definitive radiolabeled human ADME studies is an expensive and time-consuming endeavor that is more suited for later in development when the risk of failure has been reduced. We evaluated a recently developed chimeric mouse model with humanized liver on uPA/SCID background for its ability to predict human disposition of four model drugs (lamotrigine, diclofenac, MRK-A, and propafenone) that are known to exhibit human-specific metabolism. The results from these studies demonstrate that chimeric mice were able to reproduce the human-specific metabolite profile for lamotrigine, diclofenac, and MRK-A. In the case of propafenone, however, the human-specific metabolism was not detected as a predominant pathway, and the metabolite profiles in native and humanized mice were similar; this was attributed to the presence of residual highly active propafenone-metabolizing mouse enzymes in chimeric mice. Overall, the data indicate that the chimeric mice with humanized liver have the potential to be a useful tool for the prediction of human-specific metabolism of xenobiotics and warrant further investigation.

  17. Cryptogenic cirrhosis: Metabolic liver disease due to insulin resistance

    Directory of Open Access Journals (Sweden)

    Binay K De

    2010-01-01

    Full Text Available Objective: Etiopathogenesis of cryptogenic cirrhosis (CC is not yet well established. Up to 20% of non-alcoholic fatty liver disease (NAFLD may progress to cirrhosis, mostly termed as cryptogenic. Insulin resistance and altered metabolic parameters form a major pathogenic link between NAFLD and CC. CC may thus be actually a metabolic liver disease. Materials and Methods: Thirty-four patients of CC and 32 patients having cirrhosis due to chronic hepatitis B (Hep B were assessed in a cross-sectional study in a tertiary hospital for insulin resistance, % β-cell activity, obesity indices, plasma glucose, lipid profiles, and many other parameters. Results: CC patients had higher homeostasis model assessment (HOMA-IR compared to Hep B group (P = 0.000016. A positive correlation between IR values and Child-Pugh score among CC patients was found ("r" = 0.87; P < 0.00001. Out of 34 CC patients, 15 (44.1% had obesity contrary to 6 (18.8% in the control group (P = 0.0022. Differences were observed in subcutaneous fat (P = 0.0022, intra-abdominal fat (P = 0.0055, waist circumference (P = 0.014, and percentage body fat (P = 0.047 between the two groups. Significant differences were observed in the levels of triglyceride, total cholesterol, and very low density lipoprotein (VLDL. Conclusion: Most of the CC patients showed significantly higher prevalence of HOMA-IR, obesity indices, and various parameters of "lipotoxicity" and metabolic syndrome, suggesting that CC may be the long-term consequence of a type of "metabolic liver disease." Further studies are required to evaluate the role of therapeutic interventions to enhance insulin sensitivity in such patients.

  18. THE HUMAN MICROBIOTA: THE ROLE OF MICROBIAL COMMUNITIES IN HEALTH AND DISEASE

    OpenAIRE

    Luz Elena Botero Palacio; Luisa Delgado Serrano; Martha Lucía Cepeda Hernández; Patricia Del Portillo Obando; María Mercedes Zambrano Eder

    2015-01-01

    ABSTRACTDuring the last decade, there has been increasing awareness of the massive number of microorganisms, collectively known as the human microbiota, that are associated with humans. This microbiota outnumbers the host cells by approximately a factor of ten and contains a large repertoire of microbial genome-encoded metabolic processes. The diverse human microbiota and its associated metabolic potential can provide the host with novel functions that can influence host health and disease st...

  19. In Vitro Drug Metabolism by Human Carboxylesterase 1

    DEFF Research Database (Denmark)

    Thomsen, Ragnar; Rasmussen, Henrik B; Linnet, Kristian

    2014-01-01

    Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed...... a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine...... calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug...

  20. Effect of obesity and metabolic syndrome on plasma oxysterols and fatty acids in human.

    Science.gov (United States)

    Tremblay-Franco, Marie; Zerbinati, Chiara; Pacelli, Antonio; Palmaccio, Giuseppina; Lubrano, Carla; Ducheix, Simon; Guillou, Hervé; Iuliano, Luigi

    2015-07-01

    Obesity and the related entity metabolic syndrome are characterized by altered lipid metabolism and associated with increased morbidity risk for cardiovascular disease and cancer. Oxysterols belong to a large family of cholesterol-derived molecules known to play crucial role in many signaling pathways underlying several diseases. Little is known on the potential effect of obesity and metabolic syndrome on oxysterols in human. In this work, we questioned whether circulating oxysterols might be significantly altered in obese patients and in patients with metabolic syndrome. We also tested the potential correlation between circulating oxysterols and fatty acids. 60 obese patients and 75 patients with metabolic syndrome were enrolled in the study along with 210 age- and sex-matched healthy subjects, used as control group. Plasma oxysterols were analyzed by isotope dilution GC/MS, and plasma fatty acids profiling was assessed by gas chromatography coupled with flame ionization detection. We found considerable differences in oxysterols profiling in the two disease groups that were gender-related. Compared to controls, males showed significant differences only in 4α- and 4β-hydroxycholesterol levels in obese and metabolic syndrome patients. In contrast, females showed consistent differences in 7-oxocholesterol, 4α-hydroxycholesterol, 25-hydroxycholesterol and triol. Concerning fatty acids, we found minor differences in the levels of these variables in males of the three groups. Significant changes were observed in plasma fatty acid profile of female patients with obesity or metabolic syndrome. We found significant correlations between various oxysterols and fatty acids. In particular, 4β-hydroxycholesterol, which is reduced in obesity and metabolic syndrome, correlated with a number of saturated and mono-unsaturated fatty acids that are end-products of de novo lipogenesis. Our data provide the first evidence that obesity and metabolic syndrome are associated with

  1. [Alteration of biological rhythms causes metabolic diseases and obesity].

    Science.gov (United States)

    Saderi, Nadia; Escobar, Carolina; Salgado-Delgado, Roberto

    2013-07-16

    The incidence of obesity worldwide has become a serious, constantly growing public health issue that reaches alarming proportions in some countries. To date none of the strategies developed to combat obesity have proved to be decisive, and hence there is an urgent need to address the problem with new approaches. Today, studies in the field of chronobiology have shown that our physiology continually adapts itself to the cyclical changes in the environment, regard-less of whether they are daily or seasonal. This is possible thanks to the existence of a biological clock in our hypothalamus which regulates the expression and/or activity of enzymes and hormones involved in regulating our metabolism, as well as all the homeostatic functions. It has been observed that this clock can be upset as a result of today's modern lifestyle, which involves a drop in physical activity during the day and the abundant ingestion of food during the night, among other factors, which together promote metabolic syndrome and obesity. Hence, the aim of this review is to summarise the recent findings that show the effect that altering the circadian rhythms has on the metabolism and how this can play a part in the development of metabolic diseases.

  2. Modes of metabolic compensation during mitochondrial disease using the Drosophila model of ATP6 dysfunction.

    Directory of Open Access Journals (Sweden)

    Alicia M Celotto

    Full Text Available Numerous mitochondrial DNA mutations cause mitochondrial encephalomyopathy: a collection of related diseases for which there exists no effective treatment. Mitochondrial encephalomyopathies are complex multisystem diseases that exhibit a relentless progression of severity, making them both difficult to treat and study. The pathogenic and compensatory metabolic changes that are associated with chronic mitochondrial dysfunction are not well understood. The Drosophila ATP6(1 mutant models human mitochondrial encephalomyopathy and allows the study of metabolic changes and compensation that occur throughout the lifetime of an affected animal. ATP6(1animals have a nearly complete loss of ATP synthase activity and an acute bioenergetic deficit when they are asymptomatic, but surprisingly we discovered no chronic bioenergetic deficit in these animals during their symptomatic period. Our data demonstrate dynamic metabolic compensatory mechanisms that sustain normal energy availability and activity despite chronic mitochondrial complex V dysfunction resulting from an endogenous mutation in the mitochondrial DNA. ATP6(1animals compensate for their loss of oxidative phosphorylation through increases in glycolytic flux, ketogenesis and Kreb's cycle activity early during pathogenesis. However, succinate dehydrogenase activity is reduced and mitochondrial supercomplex formation is severely disrupted contributing to the pathogenesis seen in ATP6(1 animals. These studies demonstrate the dynamic nature of metabolic compensatory mechanisms and emphasize the need for time course studies in tractable animal systems to elucidate disease pathogenesis and novel therapeutic avenues.

  3. Effects of brain evolution on human nutrition and metabolism.

    Science.gov (United States)

    Leonard, William R; Snodgrass, J Josh; Robertson, Marcia L

    2007-01-01

    The evolution of large human brain size has had important implications for the nutritional biology of our species. Large brains are energetically expensive, and humans expend a larger proportion of their energy budget on brain metabolism than other primates. The high costs of large human brains are supported, in part, by our energy- and nutrient-rich diets. Among primates, relative brain size is positively correlated with dietary quality, and humans fall at the positive end of this relationship. Consistent with an adaptation to a high-quality diet, humans have relatively small gastrointestinal tracts. In addition, humans are relatively "undermuscled" and "over fat" compared with other primates, features that help to offset the high energy demands of our brains. Paleontological evidence indicates that rapid brain evolution occurred with the emergence of Homo erectus 1.8 million years ago and was associated with important changes in diet, body size, and foraging behavior.

  4. IRON METABOLISM IN THALASSEMIA AND SICKLE CELL DISEASE

    Directory of Open Access Journals (Sweden)

    Raffaella Mariani

    2009-10-01

    Full Text Available There are two main mechanisms by which iron overload develops in thalassemias: increased iron absorption due to ineffective erythropoiesis and blood transfusions. In nontransfused patients with severe thalassemia, abnormal dietary iron absorption increases body iron burden between 2 and 5 g per year. If regular transfusions are required, this doubles the rate of iron accumulation leading to earlier massive iron overload and iron-related damage. Iron metabolism largely differs between thalassemias and sickle cell disease, but chronic transfusion therapy partially normalize many of the disparities between the diseases, making iron overload an important issue to be considered in the management of patients with sickle cell disease too. The present review summarizes the actual knowledge on the regulatory pathways of iron homeostasis. In particular, the data presented indicate the inextricably link between erythropoiesis and iron metabolism and the key role of hepcidin in coordinating iron procurement according to erythropoietic requirement. The role of erythropoietin, hypoxia, erythroid-dependent soluble factors and iron in regulating hepcidin transcription are discussed as well as differences and similarities in iron homeostasis between thalassemia syndromes and sickle cell disease.

  5. Metabolic patterns in prion diseases: an FDG PET voxel-based analysis

    Energy Technology Data Exchange (ETDEWEB)

    Prieto, Elena; Dominguez-Prado, Ines; Jesus Ribelles, Maria; Arbizu, Javier [Clinica Universidad de Navarra, Nuclear Medicine Department, Pamplona (Spain); Riverol, Mario; Ortega-Cubero, Sara; Rosario Luquin, Maria; Castro, Purificacion de [Clinica Universidad de Navarra, Neurology Department, Pamplona (Spain)

    2015-09-15

    Clinical diagnosis of human prion diseases can be challenging since symptoms are common to other disorders associated with rapidly progressive dementia. In this context, {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET) might be a useful complementary tool. The aim of this study was to determine the metabolic pattern in human prion diseases, particularly sporadic Creutzfeldt-Jakob disease (sCJD), the new variant of Creutzfeldt-Jakob disease (vCJD) and fatal familial insomnia (FFI). We retrospectively studied 17 patients with a definitive, probable or possible prion disease who underwent FDG PET in our institution. Of these patients, 12 were diagnosed as sCJD (9 definitive, 2 probable and 1 possible), 1 was diagnosed as definitive vCJD and 4 were diagnosed as definitive FFI. The hypometabolic pattern of each individual and comparisons across the groups of subjects (control subjects, sCJD and FFI) were evaluated using a voxel-based analysis. The sCJD group exhibited a pattern of hypometabolism that affected both subcortical (bilateral caudate, thalamus) and cortical (frontal cortex) structures, while the FFI group only presented a slight hypometabolism in the thalamus. Individual analysis demonstrated a considerable variability of metabolic patterns among patients, with the thalamus and basal ganglia the most frequently affected areas, combined in some cases with frontal and temporal hypometabolism. Patients with a prion disease exhibit a characteristic pattern of brain metabolism presentation in FDG PET imaging. Consequently, in patients with rapidly progressive cognitive impairment, the detection of these patterns in the FDG PET study could orient the diagnosis to a prion disease. (orig.)

  6. Cardiorenal metabolic syndrome in the African diaspora: rationale for including chronic kidney disease in the metabolic syndrome definition.

    Science.gov (United States)

    Lea, Janice P; Greene, Eddie L; Nicholas, Susanne B; Agodoa, Lawrence; Norris, Keith C

    2009-01-01

    Chronic kidney disease (CKD) is more likely to progress to end-stage renal disease (ESRD) in African Americans while the reasons for this are unclear. The metabolic syndrome is a risk factor for the development of diabetes, cardiovascular disease, and has been recently linked to incident CKD. Historically, fewer African Americans meet criteria for the definition of metabolic syndrome, despite having higher rates of cardiovascular mortality than Caucasians. The presence of microalbuminuria portends increased cardiovascular risks and has been shown to cluster with the metabolic syndrome. We recently reported that proteinuria is a predictor of CKD progression in African American hypertensives with metabolic syndrome. In this review we explore the potential value of including CKD markers--microalbuminuria/proteinuria or low glomerular filtration rate (GFR)-in refining the cluster of factors defined as metabolic syndrome, ie, "cardiorenal metabolic syndrome."

  7. Genetically Modified Pig Models for Human Diseases

    Institute of Scientific and Technical Information of China (English)

    Nana Fan; Liangxue Lai

    2013-01-01

    Genetically modified animal models are important for understanding the pathogenesis of human disease and developing therapeutic strategies.Although genetically modified mice have been widely used to model human diseases,some of these mouse models do not replicate important disease symptoms or pathology.Pigs are more similar to humans than mice in anatomy,physiology,and genome.Thus,pigs are considered to be better animal models to mimic some human diseases.This review describes genetically modified pigs that have been used to model various diseases including neurological,cardiovascular,and diabetic disorders.We also discuss the development in gene modification technology that can facilitate the generation of transgenic pig models for human diseases.

  8. Comparative Analyses of QTLs Influencing Obesity and Metabolic Phenotypes in Pigs and Humans.

    Directory of Open Access Journals (Sweden)

    Sameer D Pant

    Full Text Available The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice do not completely recapitulate key pathophysiological features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564 designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits in the parental generation. Several obesity and metabolic phenotypes were recorded (n = 35 from birth to slaughter (242 ± 48 days, including body composition determined at about two months of age (63 ± 10 days via dual-energy x-ray absorptiometry (DXA scanning. All pigs were genotyped using Illumina Porcine 60k SNP Beadchip and a combined linkage disequilibrium-linkage analysis was used to identify genome-wide significant associations for collected phenotypes. We identified 229 QTLs which associated with adiposity- and metabolic phenotypes at genome-wide significant levels. Subsequently comparative analyses were performed to identify the extent of overlap between previously identified QTLs in both humans and pigs. The combined analysis of a large number of obesity phenotypes has provided insight in the genetic architecture of the molecular mechanisms underlying these traits indicating that QTLs underlying similar phenotypes are clustered in the genome. Our analyses have further confirmed that genetic heterogeneity is an inherent characteristic of obesity traits most likely caused by segregation or fixation of different variants of the individual components belonging to cellular pathways in different populations. Several important genes previously associated to obesity in human studies, along with novel genes were identified. Altogether, this study provides novel

  9. Understanding the Causes and Implications of Endothelial Metabolic Variation in Cardiovascular Disease through Genome-Scale Metabolic Modeling

    DEFF Research Database (Denmark)

    McGarrity, Sarah; Halldórsson, Haraldur; Palsson, Sirus

    2016-01-01

    of endothelial cell (EC) metabolism and its connections to cardiovascular disease (CVD) and explore the use of genome-scale metabolic models (GEMs) for integrating metabolic and genomic data. GEMs combine gene expression and metabolic data acting as frameworks for their analysis and, ultimately, afford...... mechanistic understanding of how genetic variation impacts metabolism. We demonstrate how GEMs can be used to investigate CVD-related genetic variation, drug resistance mechanisms, and novel metabolic pathways in ECs. The application of GEMs in personalized medicine is also highlighted. Particularly, we focus...... on the potential of GEMs to identify metabolic biomarkers of endothelial dysfunction and to discover methods of stratifying treatments for CVDs based on individual genetic markers. Recent advances in systems biology methodology, and how these methodologies can be applied to understand EC metabolism in both health...

  10. HIV infection results in metabolic alterations in the gut microbiota different from those induced by other diseases.

    Science.gov (United States)

    Serrano-Villar, Sergio; Rojo, David; Martínez-Martínez, Mónica; Deusch, Simon; Vázquez-Castellanos, Jorge F; Sainz, Talía; Vera, Mar; Moreno, Santiago; Estrada, Vicente; Gosalbes, María José; Latorre, Amparo; Margolles, Abelardo; Seifert, Jana; Barbas, Coral; Moya, Andrés; Ferrer, Manuel

    2016-05-18

    Imbalances in gut bacteria have been associated with multiple diseases. However, whether there are disease-specific changes in gut microbial metabolism remains unknown. Here, we demonstrate that human immunodeficiency virus (HIV) infection (n = 33) changes, at quantifiable levels, the metabolism of gut bacteria. These changes are different than those observed in patients with the auto-immune disease systemic lupus erythaematosus (n = 18), and Clostridium difficile-associated diarrhoea (n = 6). Using healthy controls as a baseline (n = 16), we demonstrate that a trend in the nature and directionality of the metabolic changes exists according to the type of the disease. The impact on the gut microbial activity, and thus the metabolite composition and metabolic flux of gut microbes, is therefore disease-dependent. Our data further provide experimental evidence that HIV infection drastically changed the microbial community, and the species responsible for the metabolism of 4 amino acids, in contrast to patients with the other two diseases and healthy controls. The identification in this present work of specific metabolic deficits in HIV-infected patients may define nutritional supplements to improve the health of these patients.

  11. MicroRNA in human cancer and chronic inflammatory diseases.

    Science.gov (United States)

    Kanwar, Jagat R; Mahidhara, Ganesh; Kanwar, Rupinder K

    2010-06-01

    MicroRNAs (miRNAs) are the non-coding RNAs that act as post-translational regulators to their complimentary messenger RNAs (mRNA). Due to their specific gene silencing property, miRNAs have been implicated in a number of cellular and developmental processes. Also, it has been proposed that a particular set of miRNA spectrum is expressed only in a particular type of tissue. Many interesting findings related to the differential expression of miRNAs in various human diseases including several types of cancers, neurodegenerative diseases and metabolic diseases have been reported. Deregulation of miRNA expression in different types of human diseases and the roles various miRNAs play as tumour suppressors as well as oncogenes, suggest their contribution to cancer and/or in other disease development. These findings have possible implications in the development of diagnostics and/or therapeutics in human malignancies. In this review, we discuss various miRNAs that are differentially expressed in human chronic inflammatory diseases, neurodegenerative diseases, cancer and the further prospective development of miRNA based diagnostics and therapeutics.

  12. The human urinary exosome as a potential metabolic effector cargo.

    Science.gov (United States)

    Bruschi, Maurizio; Ravera, Silvia; Santucci, Laura; Candiano, Giovanni; Bartolucci, Martina; Calzia, Daniela; Lavarello, Chiara; Inglese, Elvira; Petretto, Andrea; Ghiggeri, Gianmarco; Panfoli, Isabella

    2015-08-01

    Exosomes are nanovesicles, derived from the endocytic pathway, released by most cell types and found in many body fluids, including urine. A variety of exosomal functions have been reported, including transfer of RNA, cell communication, control of apoptosis and protein lifespan. Exosomes from mesenchymal stem cells can rescue bioenergetics of injured cells. Here the urinary exosome proteome, non-urinary exosome proteome and urinome are compared. A consistent number of identified proteins cluster to metabolic functions. Cytoscape software analysis based on biological processes gene ontology database shows that metabolic pathways such as aerobic glycolysis and oxidative phosphorylation have a high probability (p ≤ 0.05) of being expressed and therefore functional. A metabolic function appears to be associated with human urinary exosomes, whose relevance experimental studies can assess.

  13. Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease.

    Science.gov (United States)

    Matsuzawa, Yuji

    2006-01-01

    Abdominal fat accumulation has been shown to play crucial roles in the development of metabolic syndrome. Visceral fat accumulation particularly is closely correlated to the development of cardiovascular disease and obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension. Given these clinical findings, the functions of adipocytes have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that secrete various bioactive substances termed adipocytokines. Among adipocytokines, tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. In contrast to these adipocytokines, adiponectin, which is an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor, and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, particularly adiponectin, is discussed with respect to cardiovascular diseases.

  14. ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

    Directory of Open Access Journals (Sweden)

    Lakshini Weerasekera

    2017-01-01

    Full Text Available Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D. We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19 correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF-α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF-α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.

  15. Carotid body, insulin and metabolic diseases: unravelling the links

    Directory of Open Access Journals (Sweden)

    Silvia V Conde

    2014-10-01

    Full Text Available The carotid bodies (CB are peripheral chemoreceptors that sense changes in arterial blood O2, CO2 and pH levels. Hypoxia, hypercapnia and acidosis activate the CB, which respond by increasing the action potential frequency in their sensory nerve, the carotid sinus nerve (CSN. CSN activity is integrated in the brain stem to induce a panoply of cardiorespiratory reflexes aimed, primarily, to normalize the altered blood gases, via hyperventilation, and to regulate blood pressure and cardiac performance, via sympathetic nervous system (SNS activation. Besides its role in the cardiorespiratory control the CB has been proposed as a metabolic sensor implicated in the control of energy homeostasis and, more recently, in the regulation of whole body insulin sensitivity. Hypercaloric diets cause CB overactivation in rats, which seems to be at the origin of the development of insulin resistance and hypertension, core features of metabolic syndrome and type 2 diabetes. Consistent with this notion, CB sensory denervation prevents metabolic and hemodynamic alterations in hypercaloric feed animal. Obstructive sleep apnoea (OSA is another chronic disorder characterized by increased CB activity and intimately related with several metabolic and cardiovascular abnormalities. In this manuscript we review in a concise manner the putative pathways linking CB chemoreceptors deregulation with the pathogenesis of insulin resistance and arterial hypertension. Also, the link between chronic intermittent hypoxia (CIH and insulin resistance is discussed. Then, a final section is devoted to debate strategies to reduce CB activity and its use for prevention and therapeutics of metabolic diseases with an emphasis on new exciting research in the modulation of bioelectronic signals, likely to be central in the future.

  16. [Tree shrews under the spot light: emerging model of human diseases].

    Science.gov (United States)

    Xu, Lin; Zhang, Yun; Liang, Bin; Lü, Long-Bao; Chen, Ce-Shi; Chen, Yong-Bin; Zhou, Ju-Min; Yao, Yong-Gang

    2013-04-01

    Animal models are indispensible in biomedical research and have made tremendous contributions to answer fundamental questions on human biology, disease mechanisms, and to the development of new drugs and diagnostic tools. Due to the limitations of rodent models in translational medicine, tree shrews (Tupaia belangeri chinensis), the closest relative of primates, have attracted increasing attention in modeling human diseases and therapeutic responses. Here we discuss the recent progress in tree shrew biology and the development of tree shrews as human disease models including infectious diseases, metabolic diseases, neurological and psychiatric diseases, and cancers. Meanwhile, the current problems and future perspectives of the tree shrew model are explored.

  17. Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease.

    Science.gov (United States)

    Bogdan, Alexander R; Miyazawa, Masaki; Hashimoto, Kazunori; Tsuji, Yoshiaki

    2016-03-01

    Iron is necessary for life, but can also cause cell death. Accordingly, cells evolved a robust, tightly regulated suite of genes for maintaining iron homeostasis. Previous mechanistic studies on iron homeostasis have granted insight into the role of iron in human health and disease. We highlight new regulators of iron metabolism, including iron-trafficking proteins [solute carrier family 39, SLC39, also known as ZRT/IRT-like protein, ZIP; and poly-(rC)-binding protein, PCBP] and a cargo receptor (NCOA4) that is crucial for release of ferritin-bound iron. We also discuss emerging roles of iron in apoptosis and a novel iron-dependent cell death pathway termed 'ferroptosis', the dysregulation of iron metabolism in human pathologies, and the use of iron chelators in cancer therapy.

  18. Microvesicles/exosomes as potential novel biomarkers of metabolic diseases

    Directory of Open Access Journals (Sweden)

    Müller G

    2012-08-01

    Full Text Available Günter MüllerDepartment of Biology 1, Genetics, Ludwig-Maximilians University Munich, Biocenter, Munich, GermanyAbstract: Biomarkers are of tremendous importance for the prediction, diagnosis, and observation of the therapeutic success of common complex multifactorial metabolic diseases, such as type II diabetes and obesity. However, the predictive power of the traditional biomarkers used (eg, plasma metabolites and cytokines, body parameters is apparently not sufficient for reliable monitoring of stage-dependent pathogenesis starting with the healthy state via its initiation and development to the established disease and further progression to late clinical outcomes. Moreover, the elucidation of putative considerable differences in the underlying pathogenetic pathways (eg, related to cellular/tissue origin, epigenetic and environmental effects within the patient population and, consequently, the differentiation between individual options for disease prevention and therapy – hallmarks of personalized medicine – plays only a minor role in the traditional biomarker concept of metabolic diseases. In contrast, multidimensional and interdependent patterns of genetic, epigenetic, and phenotypic markers presumably will add a novel quality to predictive values, provided they can be followed routinely along the complete individual disease pathway with sufficient precision. These requirements may be fulfilled by small membrane vesicles, which are so-called exosomes and microvesicles (EMVs that are released via two distinct molecular mechanisms from a wide variety of tissue and blood cells into the circulation in response to normal and stress/pathogenic conditions and are equipped with a multitude of transmembrane, soluble and glycosylphosphatidylinositol-anchored proteins, mRNAs, and microRNAs. Based on the currently available data, EMVs seem to reflect the diverse functional and dysfunctional states of the releasing cells and tissues along the

  19. Metabolic Disturbances in Children with Chronic Liver Disease

    Directory of Open Access Journals (Sweden)

    A Rezaeian

    2014-04-01

    Full Text Available Introduction: Liver disease results in complex pathophysiologic disturbances affecting nutrient digestion, absorption, distribution, storage, and use. This article aimed to present a classification of metabolic disturbances in chronic liver disease in children?   Materials and Methods: In this review study databases including proquest, pubmedcentral, scincedirect, ovid, medlineplus were been searched with keyword words such as” chronic liver disease"  ” metabolic disorder””children” between 1999 to 2014. Finally, 8 related articles have been found.   Results: Metabolic disorder in this population could be categorized in four set: 1carbohydrates, 2proteins,3 fats and 4vitamins. 1 Carbohydrates: Children with CLD are at increased risk for fasting hypoglycemia, because the capacity for glycogen storage and gluconeogenesis is reduced as a result of abnormal hepatocyte function and loss of hepatocyte mass. 2 Proteins: The liver’s capacity for plasma protein synthesis is impaired by reduced substrate availability, impaired hepatocyte function, and increased catabolism. This results in hypoalbuminemia, leading to peripheral edema and contributing to ascites. Reduced synthesis of insulin-like growth factor (IGF-1 and its binding protein IGF-BP3 by the chronically diseased liver results in growth hormone resistance and may contribute to the poor growth observed in these children. 3 Fats: There is increased fat oxidation in children with end-stage liver disease in the fed and fasting states compared with controls, which is probably related to reduced carbohydrate availability. The increased lipolysis results in a decrease in fat stores, which may not be easily replenished in the setting of the fat malabsorption that accompanies cholestasis. Reduced bile delivery to the gut results in impaired fat emulsification, and hence digestion. The products of fat digestion are also poorly absorbed, because bile is also required for micelle formation

  20. Metabolic interaction between toluene, trichloroethylene and n-hexane in humans

    DEFF Research Database (Denmark)

    Bælum, Jesper; Mølhave, Lars; Hansen, S H

    1998-01-01

    This human experimental study describes the mutual metabolic interaction between toluene, trichloroethylene, and n-hexane.......This human experimental study describes the mutual metabolic interaction between toluene, trichloroethylene, and n-hexane....

  1. Uncovering disease-disease relationships through the incomplete human interactome

    Science.gov (United States)

    Menche, Jörg; Sharma, Amitabh; Kitsak, Maksim; Ghiassian, Susan; Vidal, Marc; Loscalzo, Joseph; Barabási, Albert-László

    2015-01-01

    According to the disease module hypothesis the cellular components associated with a disease segregate in the same neighborhood of the human interactome, the map of biologically relevant molecular interactions. Yet, given the incompleteness of the interactome and the limited knowledge of disease-associated genes, it is not obvious if the available data has sufficient coverage to map out modules associated with each disease. Here we derive mathematical conditions for the identifiability of disease modules and show that the network-based location of each disease module determines its pathobiological relationship to other diseases. For example, diseases with overlapping network modules show significant co-expression patterns, symptom similarity, and comorbidity, while diseases residing in separated network neighborhoods are clinically distinct. These tools represent an interactome-based platform to predict molecular commonalities between clinically related diseases, even if they do not share disease genes. PMID:25700523

  2. Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population

    Directory of Open Access Journals (Sweden)

    Ellis James K

    2012-06-01

    Full Text Available Abstract Background The 'exposome' represents the accumulation of all environmental exposures across a lifetime. Top-down strategies are required to assess something this comprehensive, and could transform our understanding of how environmental factors affect human health. Metabolic profiling (metabonomics/metabolomics defines an individual's metabolic phenotype, which is influenced by genotype, diet, lifestyle, health and xenobiotic exposure, and could also reveal intermediate biomarkers for disease risk that reflect adaptive response to exposure. We investigated changes in metabolism in volunteers living near a point source of environmental pollution: a closed zinc smelter with associated elevated levels of environmental cadmium. Methods High-resolution 1H NMR spectroscopy (metabonomics was used to acquire urinary metabolic profiles from 178 human volunteers. The spectral data were subjected to multivariate and univariate analysis to identify metabolites that were correlated with lifestyle or biological factors. Urinary levels of 8-oxo-deoxyguanosine were also measured, using mass spectrometry, as a marker of systemic oxidative stress. Results Six urinary metabolites, either associated with mitochondrial metabolism (citrate, 3-hydroxyisovalerate, 4-deoxy-erythronic acid or one-carbon metabolism (dimethylglycine, creatinine, creatine, were associated with cadmium exposure. In particular, citrate levels retained a significant correlation to urinary cadmium and smoking status after controlling for age and sex. Oxidative stress (as determined by urinary 8-oxo-deoxyguanosine levels was elevated in individuals with high cadmium exposure, supporting the hypothesis that heavy metal accumulation was causing mitochondrial dysfunction. Conclusions This study shows evidence that an NMR-based metabolic profiling study in an uncontrolled human population is capable of identifying intermediate biomarkers of response to toxicants at true environmental

  3. Endocrine manifestations related to inherited metabolic diseases in adults

    Directory of Open Access Journals (Sweden)

    Vantyghem Marie-Christine

    2012-01-01

    Full Text Available Abstract Most inborn errors of metabolism (IEM are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.. IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects, and metal (hemochromatosis and storage disorders (cystinosis. Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes, whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure, congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last. This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses.

  4. Assessing the Metabolic Effects of Aromatherapy in Human Volunteers

    Directory of Open Access Journals (Sweden)

    Yinan Zhang

    2013-01-01

    Full Text Available Aromatherapy, a form of complementary and alternative medicine (CAM that uses essential oils through inhalation, is believed to enhance physical and spiritual conditions. Although clinical studies suggest that the use of essential oils may have therapeutic potential, evidence for the efficacy of aromatherapy in treating medical conditions remains poor, with a particular lack of studies employing rigorous analytical methods that capture its identifiable impact on human biology. Here, we report a comprehensive metabolomics study that reveals metabolic changes in people after exposed to aroma inhalation for 10 continuous days. In this study, the metabolic alterations in urine of 31 females with mild anxiety symptoms exposed to aerial diffusion of aromas were measured by GC-TOF-MS and UPLC-Q-TOF-MS analyses. A significant alteration of metabolic profile in subjects responsive to essential oil was found, which is characterized by the increased levels of arginine, homocysteine, and betaine, as well as decreased levels of alcohols, carbohydrates, and organic acids in urine. Notably, the metabolites from tricarboxylic acid (TCA cycle and gut microbial metabolism were significantly altered. This study demonstrates that the metabolomics approach can capture the subtle metabolic changes resulting from exposure to essential oils, which may lead to an improved mechanistic understanding of aromatherapy.

  5. Vegetarian diets and gut microbiota: important shifts in markers of metabolism and cardiovascular disease.

    Science.gov (United States)

    do Rosario, Vinicius A; Fernandes, Ricardo; Trindade, Erasmo B S de M

    2016-07-01

    Vegetarian diets have been associated with a lower incidence of several chronic diseases. The benefits of plant-based diets are related mainly to the improvement of metabolic parameters that can indicate risk for such diseases. Some metabolic factors, such as oxidative balance, lipid profile, and glucose homeostasis, can be improved directly by diet, but paradoxically, some characteristics of vegetarian diets may promote a negative scenario that increases the risk of certain chronic diseases. Additionally, many benefits of a vegetarian diet are mediated by the gut microbiota, members of which not only have taxonomic and functional differences but also produce diverse, specific metabolites that vary according to whether the host consumes an omnivorous or a vegetarian diet. This review examines the modulation of human metabolism and gut microbiota by vegetarian and omnivorous dietary patterns and explores how this modulation may affect the risk of cardiovascular disease. © The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. A novel untargeted metabolomics correlation-based network analysis incorporating human metabolic reconstructions.

    Science.gov (United States)

    Kotze, Helen L; Armitage, Emily G; Sharkey, Kieran J; Allwood, James W; Dunn, Warwick B; Williams, Kaye J; Goodacre, Royston

    2013-10-23

    Metabolomics has become increasingly popular in the study of disease phenotypes and molecular pathophysiology. One branch of metabolomics that encompasses the high-throughput screening of cellular metabolism is metabolic profiling. In the present study, the metabolic profiles of different tumour cells from colorectal carcinoma and breast adenocarcinoma were exposed to hypoxic and normoxic conditions and these have been compared to reveal the potential metabolic effects of hypoxia on the biochemistry of the tumour cells; this may contribute to their survival in oxygen compromised environments. In an attempt to analyse the complex interactions between metabolites beyond routine univariate and multivariate data analysis methods, correlation analysis has been integrated with a human metabolic reconstruction to reveal connections between pathways that are associated with normoxic or hypoxic oxygen environments. Correlation analysis has revealed statistically significant connections between metabolites, where differences in correlations between cells exposed to different oxygen levels have been highlighted as markers of hypoxic metabolism in cancer. Network mapping onto reconstructed human metabolic models is a novel addition to correlation analysis. Correlated metabolites have been mapped onto the Edinburgh human metabolic network (EHMN) with the aim of interlinking metabolites found to be regulated in a similar fashion in response to oxygen. This revealed novel pathways within the metabolic network that may be key to tumour cell survival at low oxygen. Results show that the metabolic responses to lowering oxygen availability can be conserved or specific to a particular cell line. Network-based correlation analysis identified conserved metabolites including malate, pyruvate, 2-oxoglutarate, glutamate and fructose-6-phosphate. In this way, this method has revealed metabolites not previously linked, or less well recognised, with respect to hypoxia before. Lactate

  7. Regulation of Metabolic Signaling in Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Albers, Peter Hjorth

    sensitivity in type I muscle fibers possibly reflects a superior effect of insulin on metabolic signaling compared to type II muscle fibers. This was investigated in the present thesis by examining muscle biopsies from lean and obese healthy subjects as well as patients with type 2 diabetes. From these muscle...... enzymes. Skeletal muscle consists of thousands of muscle fibers. These fibers can roughly be classified into type I and type II muscle fibers. The overall aim of this PhD thesis was to investigate the effect of insulin and exercise on human muscle fiber type specific metabolic signaling. The importance...... of human type I muscle fibers is illustrated by the finding of a positive correlation between the relative distribution of type I fibers in the muscle and whole-body insulin sensitivity. This suggests, that type I muscle fibers are more insulin sensitive than type II muscle fibers. Improved insulin...

  8. Metabolism of Cartilage Proteoglycans in Health and Disease

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    Demitrios H. Vynios

    2014-01-01

    Full Text Available Cartilage proteoglycans are extracellular macromolecules with complex structure, composed of a core protein onto which a variable number of glycosaminoglycan chains are attached. Their biosynthesis at the glycosaminoglycan level involves a great number of sugar transferases well-orchestrated in Golgi apparatus. Similarly, their degradation, either extracellular or intracellular in lysosomes, involves a large number of hydrolases. A deficiency or malfunction of any of the enzymes participating in cartilage proteoglycan metabolism may lead to severe disease state. This review summarizes the findings regarding this topic.

  9. Does biodiversity protect humans against infectious disease?

    Science.gov (United States)

    Wood, Chelsea L; Lafferty, Kevin D; DeLeo, Giulio; Young, Hillary S; Hudson, Peter J; Kuris, Armand M

    2014-04-01

    Control of human infectious disease has been promoted as a valuable ecosystem service arising from the conservation of biodiversity. There are two commonly discussed mechanisms by which biodiversity loss could increase rates of infectious disease in a landscape. First, loss of competitors or predators could facilitate an increase in the abundance of competent reservoir hosts. Second, biodiversity loss could disproportionately affect non-competent, or less competent reservoir hosts, which would otherwise interfere with pathogen transmission to human populations by, for example, wasting the bites of infected vectors. A negative association between biodiversity and disease risk, sometimes called the "dilution effect hypothesis," has been supported for a few disease agents, suggests an exciting win-win outcome for the environment and society, and has become a pervasive topic in the disease ecology literature. Case studies have been assembled to argue that the dilution effect is general across disease agents. Less touted are examples in which elevated biodiversity does not affect or increases infectious disease risk for pathogens of public health concern. In order to assess the likely generality of the dilution effect, we review the association between biodiversity and public health across a broad variety of human disease agents. Overall, we hypothesize that conditions for the dilution effect are unlikely to be met for most important diseases of humans. Biodiversity probably has little net effect on most human infectious diseases but, when it does have an effect, observation and basic logic suggest that biodiversity will be more likely to increase than to decrease infectious disease risk.

  10. Human genetic variation and the gut microbiome in disease.

    Science.gov (United States)

    Hall, Andrew Brantley; Tolonen, Andrew C; Xavier, Ramnik J

    2017-08-21

    Taxonomic and functional changes to the composition of the gut microbiome have been implicated in multiple human diseases. Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome. Although many factors can affect the microbial organisms residing in the gut, a number of recent findings support the hypothesis that certain host genetic variants predispose an individual towards microbiome dysbiosis. This condition, in which the normal microbiome population structure is disturbed, is a key feature in disorders of metabolism and immunity.

  11. Metabolic thrift and the genetic basis of human obesity

    OpenAIRE

    O’Rourke, Robert W.

    2014-01-01

    Evolution has molded metabolic thrift within humans, a genetic heritage that, when thrust into our modern “obesogenic” environment, creates the current obesity crisis. Modern genetic analysis has identified genetic and epigenetic contributors to obesity, an understanding of which will guide the development of environmental, pharmacologic, and genetic therapeutic interventions. “The voyage was so long, food and water ran out. One hundred of the paddlers died; forty men remained. The voyager...

  12. [Metabolism of mitomycin C by human liver microsomes in vitro].

    Science.gov (United States)

    Hao, Fu-rong; Yan, Min-fen; Hu, Zhuo-han; Jin, Yi-zun

    2007-02-01

    To provide the profiles of metabolism of mitomycin C (MMC) by human liver microsomes in vitro, MMC was incubated with human liver microsomes, then the supernatant component was isolated and detected by HPLC. Types of metabolic enzymes were estimated by the effect of NADPH or dicumarol (DIC) on metabolism of MMC. Standard, reaction, background control (microsomes was inactivated), negative control (no NADPH), and inhibitor group (adding DIC) were assigned, the results were analyzed by Graphpad Prism 4. 0 software. Reaction group compared with background control and negative control groups, 3 NADPH-dependent absorption peaks were additionally isolated by HPLC after MMC were incubated with human liver microsomes. Their retention times were 10. 0, 14. 0, 14. 8 min ( named as Ml, M2, M3) , respectively. Their formation was kept as Sigmoidal dose-response and their Km were 0. 52 (95% CI, 0. 40 - 0.67) mmol x L(-1), 0. 81 (95% CI, 0. 59 - 1. 10) mmol x L(-1), 0. 54 (95% CI, 0. 41 -0. 71) mmol x L(-1) , respectively. The data indicated that the three absorption peaks isolated by HPLC were metabolites of MMC. DIC can inhibit formation of M2, it' s dose-effect fitted to Sigmoidal curve and it' s IC50 was 59. 68 (95% CI, 40. 66 - 87. 61) micromol x L(-1) , which indicated DT-diaphorase could take part in the formation of M2. MMC can be metabolized by human liver microsomes in vitro, and at least three metabolites of MMC could be isolated by HPLC in the experiment, further study showed DT-diaphorase participated in the formation of M2.

  13. A metabolic system-wide characterisation of the pig: a model for human physiology.

    Science.gov (United States)

    Merrifield, Claire A; Lewis, Marie; Claus, Sandrine P; Beckonert, Olaf P; Dumas, Marc-Emmanuel; Duncker, Swantje; Kochhar, Sunil; Rezzi, Serge; Lindon, John C; Bailey, Mick; Holmes, Elaine; Nicholson, Jeremy K

    2011-09-01

    The pig is a single-stomached omnivorous mammal and is an important model of human disease and nutrition. As such, it is necessary to establish a metabolic framework from which pathology-based variation can be compared. Here, a combination of one and two-dimensional (1)H and (13)C nuclear magnetic resonance spectroscopy (NMR) and high-resolution magic angle spinning (HR-MAS) NMR was used to provide a systems overview of porcine metabolism via characterisation of the urine, serum, liver and kidney metabolomes. The metabolites observed in each of these biological compartments were found to be qualitatively comparable to the metabolic signature of the same biological matrices in humans and rodents. The data were modelled using a combination of principal components analysis and Venn diagram mapping. Urine represented the most metabolically distinct biological compartment studied, with a relatively greater number of NMR detectable metabolites present, many of which are implicated in gut-microbial co-metabolic processes. The major inter-species differences observed were in the phase II conjugation of extra-genomic metabolites; the pig was observed to conjugate p-cresol, a gut microbial metabolite of tyrosine, with glucuronide rather than sulfate as seen in man. These observations are important to note when considering the translatability of experimental data derived from porcine models.

  14. Mitochondrial proteomics on human fibroblasts for identification of metabolic imbalance and cellular stress

    Directory of Open Access Journals (Sweden)

    Bross Peter

    2009-05-01

    Full Text Available Abstract Background Mitochondrial proteins are central to various metabolic activities and are key regulators of apoptosis. Disturbance of mitochondrial proteins is therefore often associated with disease. Large scale protein data are required to capture the mitochondrial protein levels and mass spectrometry based proteomics is suitable for generating such data. To study the relative quantities of mitochondrial proteins in cells from cultivated human skin fibroblasts we applied a proteomic method based on nanoLC-MS/MS analysis of iTRAQ-labeled peptides. Results When fibroblast cultures were exposed to mild metabolic stress – by cultivation in galactose medium- the amount of mitochondria appeared to be maintained whereas the levels of individual proteins were altered. Proteins of respiratory chain complex I and IV were increased together with NAD+-dependent isocitrate dehydrogenase of the citric acid cycle illustrating cellular strategies to cope with altered energy metabolism. Furthermore, quantitative protein data, with a median standard error below 6%, were obtained for the following mitochondrial pathways: fatty acid oxidation, citric acid cycle, respiratory chain, antioxidant systems, amino acid metabolism, mitochondrial translation, protein quality control, mitochondrial morphology and apoptosis. Conclusion The robust analytical platform in combination with a well-defined compendium of mitochondrial proteins allowed quantification of single proteins as well as mapping of entire pathways. This enabled characterization of the interplay between metabolism and stress response in human cells exposed to mild stress.

  15. Degeneration of dopaminergic neurons due to metabolic alterations and Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Juhyun eSong

    2016-03-01

    Full Text Available The rates of metabolic diseases, such as type 2 diabetes mellitus (T2DM, obesity, and cardiovascular disease, markedly increase with age. In recent years, studies have reported an association between metabolic changes and various pathophysiological mechanisms in the central nervous system (CNS in patients with metabolic diseases. Oxidative stress and hyperglycemia in metabolic diseases lead to adverse neurophysiological phenomena, including neuronal loss, synaptic dysfunction, and improper insulin signaling, resulting in Parkinson’s disease (PD. In addition, several lines of evidence suggest that alterations of CNS environments by metabolic changes influence the dopamine neuronal loss, eventually affecting the pathogenesis of PD. Thus, we reviewed recent findings relating to degeneration of dopaminergic neurons during metabolic diseases. We highlight the fact that using a metabolic approach to manipulate degeneration of dopaminergic neurons can serve as a therapeutic strategy to attenuate pathology of PD.

  16. Metabolic abnormalities in patients with inflammatory rheumatic diseases.

    Science.gov (United States)

    Dessein, Patrick H; Solomon, Ahmed; Hollan, Ivana

    2016-10-01

    Patients with rheumatoid arthritis (RA) experience an increased cardiometabolic risk factor burden that is substantially driven by systemic inflammation. This occurs less consistently in patients with ankylosing spondylitis (AS). Psoriatic arthritis most strongly associates with excess adiposity and metabolic risk. RA patients also often have systemic inflammation-induced proinflammatory high-density lipoprotein (HDL) cholesterol particles and lean/muscle mass loss in association with increased adiposity, a condition termed rheumatoid cachexia, which further enhances cardiovascular risk. The presence of proinflammatory HDL and lean mass loss was also reported in patients with AS. Individualized aerobic and resistance exercise programs can improve body composition and metabolic risk factor profiles in RA and AS. Future studies should assess how long-term lifestyle changes can be effectuated and if these can influence cardiovascular events in inflammatory rheumatic diseases. Herein, we review the current evidence on metabolic abnormalities in inflammatory arthritis. We propose management strategies and a research agenda. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Cyclic vomiting syndrome masking a fatal metabolic disease.

    LENUS (Irish Health Repository)

    Fitzgerald, Marianne

    2013-05-01

    Disorders of fatty acid oxidation are rare but can be fatal. Hypoglycaemia with acidosis is a cardinal feature. Cases may present during early childhood or can be delayed into adolescence or beyond. We present a case of multiple acyl-coenzyme A dehydrogenase deficiency (MADD), an extremely rare disorder of fatty acid oxidation. Our 20-year-old patient presented with cardiovascular collapse, raised anion gap metabolic acidosis and non-ketotic hypoglycaemia. She subsequently developed multi-organ failure and sadly died. She had a previous diagnosis of cyclic vomiting syndrome (CVS) for more than 10 years, warranting frequent hospital admissions. The association between CVS and MADD has been made before though the exact relationship is unclear. All patients with persistent severe CVS should have metabolic investigations to exclude disorders of fatty acid oxidation. In case of non-ketotic hypoglycaemia with acidosis, the patient should be urgently referred to a specialist in metabolic diseases. All practitioners should be aware of these rare disorders as a cause of unexplained acidosis.

  18. Parasitic diseases in humans transmitted by vectors.

    Science.gov (United States)

    Cholewiński, Marcin; Derda, Monika; Hadaś, Edward

    2015-01-01

    Despite the considerable progress of medicine, parasitic diseases still pose a great threat to human health and life. Among parasitic diseases, those transmitted by vectors, mainly arthropods, play a particular role. These diseases occur most frequently in the poorest countries and affect a vast part of the human population. They include malaria, babesiosis, trypanosomiasis, leishmaniasis and filariasis. This study presents those vector-transmitted diseases that are responsible for the greatest incidence and mortality of people on a global scale. Attention is focused primarily on diseases transmitted by mosquitoes, flies, Hemiptera and ticks.

  19. Prevention of postprandial metabolic stress in humans: role of fruit-derived products.

    Science.gov (United States)

    Morabito, Giuseppa; Kucan, Petra; Serafini, Mauro

    2015-01-01

    The consumption of unbalanced meals, consisting of foods rich in lipids and/or carbohydrates and calories, has been associated to a postprandial metabolic stress that involves the increase of the production of free radicals and proinflammatory markers. Growing evidence suggest that dietary polyphenols contained in fruit-derived products, such as fruit juices, are involved in the role played by plant foods in disease prevention. Their association to a calorie-dense meal may help to attenuate the onset of postprandial metabolic and inflammatory stress. The available evidence in the literature investigating the effects of polyphenols rich fruit juices on the modulation of postprandial-induced metabolic stress in humans will be presented and discussed.

  20. Downregulation of sulfotransferase expression and activity in diseased human livers.

    Science.gov (United States)

    Yalcin, Emine B; More, Vijay; Neira, Karissa L; Lu, Zhenqiang James; Cherrington, Nathan J; Slitt, Angela L; King, Roberta S

    2013-09-01

    Sulfotransferase (SULT) function has been well studied in healthy human subjects by quantifying mRNA and protein expression and determining enzyme activity with probe substrates. However, it is not well known if sulfotransferase activity changes in metabolic and liver disease, such as diabetes, steatosis, or cirrhosis. Sulfotransferases have significant roles in the regulation of hormones and excretion of xenobiotics. In the present study of normal subjects with nonfatty livers and patients with steatosis, diabetic cirrhosis, and alcoholic cirrhosis, we sought to determine SULT1A1, SULT2A1, SULT1E1, and SULT1A3 activity and mRNA and protein expression in human liver tissue. In general, sulfotransferase activity decreased significantly with severity of liver disease from steatosis to cirrhosis. Specifically, SULT1A1 and SULT1A3 activities were lower in disease states relative to nonfatty tissues. Alcoholic cirrhotic tissues further contained lower SULT1A1 and 1A3 activities than those affected by either of the two other disease states. SULT2A1, on the other hand, was only reduced in alcoholic cirrhotic tissues. SULT1E1 was reduced both in diabetic cirrhosis and in alcoholic cirrhosis tissues, relative to nonfatty liver tissues. In conclusion, the reduced levels of sulfotransferase expression and activity in diseased versus nondiseased liver tissue may alter the metabolism and disposition of xenobiotics and affect homeostasis of endobiotic sulfotransferase substrates.

  1. Aspartate aminotransferase – key enzyme in the human systemic metabolism

    Directory of Open Access Journals (Sweden)

    Dagmara Otto-Ślusarczyk

    2016-03-01

    Full Text Available Aspartate aminotransferase is an organ - nonspecific enzyme located in many tissues of the human body where it catalyzes reversible reaction of transamination. There are two aspartate aminotransferase isoforms - cytoplasmic (AST1 and mitochondrial (AST2, that usually occur together and interact with each other metabolically. Both isoforms are homodimers containing highly conservative regions responsible for catalytic properties of enzyme. The common feature of all aspartate aminotransfeses is Lys – 259 residue covalent binding with prosthetic group - pyridoxal phosphate. The differences in the primary structure of AST isoforms determine their physico-chemical, kinetic and immunological properties. Because of the low concentration of L-aspartate (L-Asp in the blood, AST is the only enzyme, which supply of this amino acid as a substrate for many metabolic processes, such as urea cycle or purine and pyrimidine nucleotides in the liver, synthesis of L-arginine in the kidney and purine nucleotide cycle in the brain and the skeletal muscle. AST is also involved in D-aspartate production that regulates the metabolic activity at the auto-, para- and endocrine level. Aspartate aminotransferase is a part of the malate-aspartate shuttle in the myocardium, is involved in gluconeogenesis in the liver and kidney, glyceroneogenesis in the adipose tissue, and synthesis of neurotransmitters and neuro-glial pathway in the brain. Recently, the significant role of AST in glutaminolysis - normal metabolic pathway in tumor cells, was demonstrated. The article is devoted the role of AST, known primarily as a diagnostic liver enzyme, in metabolism of various human tissues and organs.

  2. Systems biology study of mucopolysaccharidosis using a human metabolic reconstruction network.

    Science.gov (United States)

    Salazar, Diego A; Rodríguez-López, Alexander; Herreño, Angélica; Barbosa, Hector; Herrera, Juliana; Ardila, Andrea; Barreto, George E; González, Janneth; Alméciga-Díaz, Carlos J

    2016-02-01

    Mucopolysaccharidosis (MPS) is a group of lysosomal storage diseases (LSD), characterized by the deficiency of a lysosomal enzyme responsible for the degradation of glycosaminoglycans (GAG). This deficiency leads to the lysosomal accumulation of partially degraded GAG. Nevertheless, deficiency of a single lysosomal enzyme has been associated with impairment in other cell mechanism, such as apoptosis and redox balance. Although GAG analysis represents the main biomarker for MPS diagnosis, it has several limitations that can lead to a misdiagnosis, whereby the identification of new biomarkers represents an important issue for MPS. In this study, we used a system biology approach, through the use of a genome-scale human metabolic reconstruction to understand the effect of metabolism alterations in cell homeostasis and to identify potential new biomarkers in MPS. In-silico MPS models were generated by silencing of MPS-related enzymes, and were analyzed through a flux balance and variability analysis. We found that MPS models used approximately 2286 reactions to satisfy the objective function. Impaired reactions were mainly involved in cellular respiration, mitochondrial process, amino acid and lipid metabolism, and ion exchange. Metabolic changes were similar for MPS I and II, and MPS III A to C; while the remaining MPS showed unique metabolic profiles. Eight and thirteen potential high-confidence biomarkers were identified for MPS IVB and VII, respectively, which were associated with the secondary pathologic process of LSD. In vivo evaluation of predicted intermediate confidence biomarkers (β-hexosaminidase and β-glucoronidase) for MPS IVA and VI correlated with the in-silico prediction. These results show the potential of a computational human metabolic reconstruction to understand the molecular mechanisms this group of diseases, which can be used to identify new biomarkers for MPS.

  3. Epicardial adipose tissue in endocrine and metabolic diseases.

    Science.gov (United States)

    Iacobellis, Gianluca

    2014-05-01

    Epicardial adipose tissue has recently emerged as new risk factor and active player in metabolic and cardiovascular diseases. Albeit its physiological and pathological roles are not completely understood, a body of evidence indicates that epicardial adipose tissue is a fat depot with peculiar and unique features. Epicardial fat is able to synthesize, produce, and secrete bioactive molecules which are then transported into the adjacent myocardium through vasocrine and/or paracrine pathways. Based on these evidences, epicardial adipose tissue can be considered an endocrine organ. Epicardial fat is also thought to provide direct heating to the myocardium and protect the heart during unfavorable hemodynamic conditions, such as ischemia or hypoxia. Epicardial fat has been suggested to play an independent role in the development and progression of obesity- and diabetes-related cardiac abnormalities. Clinically, the thickness of epicardial fat can be easily and accurately measured. Epicardial fat thickness can serve as marker of visceral adiposity and visceral fat changes during weight loss interventions and treatments with drugs targeting the fat. The potential of modulating the epicardial fat with targeted pharmacological agents can open new avenues in the pharmacotherapy of endocrine and metabolic diseases. This review article will provide Endocrine's reader with a focus on epicardial adipose tissue in endocrinology. Novel, established, but also speculative findings on epicardial fat will be discussed from the unexplored perspective of both clinical and basic Endocrinologist.

  4. Determinants of increased cardiovascular disease in obesity and metabolic syndrome.

    Science.gov (United States)

    Vazzana, N; Santilli, F; Sestili, S; Cuccurullo, C; Davi, G

    2011-01-01

    Obesity is associated with an increased mortality and morbidity for cardiovascular disease (CVD) and adipose tissue is recognised as an important player in obesity-mediated CVD. The diagnosis of the metabolic syndrome (MS) appears to identify substantial additional cardiovascular risk above and beyond the individual risk factors, even though the pathophysiology underlying this evidence is still unravelled. The inflammatory response related to fat accumulation may influence cardiovascular risk through its involvement not only in body weight homeostasis, but also in coagulation, fibrinolysis, endothelial dysfunction, insulin resistance (IR) and atherosclerosis. Moreover, there is evidence that oxidative stress may be a mechanistic link between several components of MS and CVD, through its role in inflammation and its ability to disrupt insulin-signaling. The cross-talk between impaired insulin-signaling and inflammatory pathways enhances both metabolic IR and endothelial dysfunction, which synergize to predispose to CVD. Persistent platelet hyperreactivity/activation emerges as the final pathway driven by intertwined interactions among IR, adipokine release, inflammation, dyslipidemia and oxidative stress and provides a pathophysiological explanation for the excess risk of atherothrombosis in this setting. Despite the availability of multiple interventions to counteract these metabolic changes, including appropriate diet, regular exercise, antiobesity drugs and bariatric surgery, relative failure to control the incidence of MS and its complications reflects both the multifactorial nature of these diseases as well as the scarce compliance of patients to established strategies. Evaluation of the impact of these therapeutic strategies on the pathobiology of atherothrombosis, as discussed in this review, will translate into an optimized approach for cardiovascular prevention.

  5. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms.

    Science.gov (United States)

    Guo, Shaodong

    2014-02-01

    Insulin resistance is a major underlying mechanism responsible for the 'metabolic syndrome', which is also known as insulin resistance syndrome. The incidence of the metabolic syndrome is increasing at an alarming rate, becoming a major public and clinical problem worldwide. The metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies have demonstrated that insulin and its signaling cascade normally control cell growth, metabolism, and survival through the activation of MAPKs and activation of phosphatidylinositide-3-kinase (PI3K), in which the activation of PI3K associated with insulin receptor substrate 1 (IRS1) and IRS2 and subsequent Akt→Foxo1 phosphorylation cascade has a central role in the control of nutrient homeostasis and organ survival. The inactivation of Akt and activation of Foxo1, through the suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and overnutrition, may act as the underlying mechanisms for the metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will probably provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the features of the metabolic syndrome. Emphasis is placed on the role of IRS1, IRS2, and associated signaling pathways that are coupled to Akt and the forkhead/winged helix transcription factor Foxo1.

  6. Insulin Signaling, Resistance, and the Metabolic Syndrome: Insights from Mouse Models to Disease Mechanisms

    Science.gov (United States)

    Guo, Shaodong

    2014-01-01

    Insulin resistance is a major underlying mechanism for the “metabolic syndrome”, which is also known as insulin resistance syndrome. Metabolic syndrome is increasing at an alarming rate, becoming a major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies demonstrate that insulin and its signaling cascade normally control cell growth, metabolism and survival through activation of mitogen-activated protein kinases (MAPKs) and phosphotidylinositide-3-kinase (PI3K), of which activation of PI-3K-associated with insulin receptor substrate-1 and -2 (IRS1, 2) and subsequent Akt→Foxo1 phosphorylation cascade has a central role in control of nutrient homeostasis and organ survival. Inactivation of Akt and activation of Foxo1, through suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and over nutrition may provide the underlying mechanisms for metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will likely provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the feature of the metabolic syndrome. Emphasis will be placed on the role of IRS1, IRS2, and associated signaling pathways that couple to Akt and the forkhead/winged helix transcription factor Foxo1. PMID:24281010

  7. Optimizing human hepatocyte models for metabolic phenotype and function: effects of treatment with dimethyl sulfoxide (DMSO).

    Science.gov (United States)

    Nikolaou, Nikolaos; Green, Charlotte J; Gunn, Pippa J; Hodson, Leanne; Tomlinson, Jeremy W

    2016-11-01

    Primary human hepatocytes are considered to be the "gold standard" cellular model for studying hepatic fatty acid and glucose metabolism; however, they come with limitations. Although the HepG2 cell line retains many of the primary hepatocyte metabolic functions they have a malignant origin and low rates of triglyceride secretion. The aim of this study was to investigate whether dimethyl sulfoxide supplementation in the media of HepG2 cells would enhance metabolic functionality leading to the development of an improved in vitro cell model that closely recapitulates primary human hepatocyte metabolism. HepG2 cells were cultured in media containing 1% dimethyl sulfoxide for 2, 4, 7, 14, and 21 days. Gene expression, protein levels, intracellular triglyceride, and media concentrations of triglyceride, urea, and 3-hydroxybutyrate concentrations were measured. Dimethyl sulfoxide treatment altered the expression of genes involved in lipid (FAS, ACC1, ACC2, DGAT1, DGAT2, SCD) and glucose (PEPCK, G6Pase) metabolism as well as liver functionality (albumin, alpha-1-antitrypsin, AFP). mRNA changes were paralleled by alterations at the protein level. DMSO treatment decreased intracellular triglyceride content and lactate production and increased triglyceride and 3-hydroxybutyrate concentrations in the media in a time-dependent manner. We have demonstrated that the addition of 1% dimethyl sulfoxide to culture media changes the metabolic phenotype of HepG2 cells toward a more primary human hepatocyte phenotype. This will enhance the currently available in vitro model systems for the study of hepatocyte biology related to pathological processes that contribute to disease and their response to specific therapeutic interventions. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  8. Effect of metabolic alkalosis on respiratory function in patients with chronic obstructive lung disease.

    Science.gov (United States)

    Bear, R.; Goldstein, M.; Phillipson, E.; Ho, M.; Hammeke, M.; Feldman, R.; Handelsman, S.; Halperin, M.

    1977-01-01

    Eleven instances of a mixed acid-base disorder consisting of chronic respiratory acidosis and metabolic alkalosis were recognized in eight patients with chronic obstructive lung disease and carbon dioxide retention. Correction of the metabolic alkalosis led to substantial improvement in blood gas values and clinical symptoms. Patients with mixed chronic respiratory acidosis and metabolic alkalosis constitute a common subgroup of patients with chronic obstructive lung disease and carbon dioxide retention; these patients benefit from correction of the metabolic alkalosis. PMID:21028

  9. Molecular mechanisms of acrolein toxicity: relevance to human disease.

    Science.gov (United States)

    Moghe, Akshata; Ghare, Smita; Lamoreau, Bryan; Mohammad, Mohammad; Barve, Shirish; McClain, Craig; Joshi-Barve, Swati

    2015-02-01

    Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and its potential as a serious environmental health threat is beginning to be recognized. Humans are exposed to acrolein per oral (food and water), respiratory (cigarette smoke, automobile exhaust, and biocide use) and dermal routes, in addition to endogenous generation (metabolism and lipid peroxidation). Acrolein has been suggested to play a role in several disease states including spinal cord injury, multiple sclerosis, Alzheimer's disease, cardiovascular disease, diabetes mellitus, and neuro-, hepato-, and nephro-toxicity. On the cellular level, acrolein exposure has diverse toxic effects, including DNA and protein adduction, oxidative stress, mitochondrial disruption, membrane damage, endoplasmic reticulum stress, and immune dysfunction. This review addresses our current understanding of each pathogenic mechanism of acrolein toxicity, with emphasis on the known and anticipated contribution to clinical disease, and potential therapies.

  10. Metabolism

    Science.gov (United States)

    ... Surgery? Choosing the Right Sport for You Shyness Metabolism KidsHealth > For Teens > Metabolism Print A A A ... food through a process called metabolism. What Is Metabolism? Metabolism (pronounced: meh-TAB-uh-lih-zem) is ...

  11. Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease: A Dynamic and Life-Threatening Triad

    Directory of Open Access Journals (Sweden)

    Mário Raimundo

    2011-01-01

    Full Text Available The metabolic syndrome (MS and chronic kidney disease (CKD have both become global public health problems, with increasing social and economic impact due to their high prevalence and remarkable impact on morbidity and mortality. The causality between MS and CKD, and its clinical implications, still does remain not completely understood. Moreover, prophylactic and therapeutic interventions do need to be properly investigated in this field. Herein, we critically review the existing clinical evidence that associates MS with renal disease and cardiovascular disease, as well as the associated pathophysiologic mechanisms and actual treatment options.

  12. Stem cell differentiation and human liver disease

    Institute of Scientific and Technical Information of China (English)

    Wen-Li Zhou; Claire N Medine; Liang Zhu; David C Hay

    2012-01-01

    Human stem cells are scalable cell populations capable of cellular differentiation.This makes them a very attractive in vitro cellular resource and in theory provides unlimited amounts of primary cells.Such an approach has the potential to improve our understanding of human biology and treating disease.In the future it may be possible to deploy novel stem cell-based approaches to treat human liver diseases.In recent years,efficient hepatic differentiation from human stem cells has been achieved by several research groups including our own.In this review we provide an overview of the field and discuss the future potential and limitations of stem cell technology.

  13. Molecular clocks and the human condition: approaching their characterization in human physiology and disease.

    Science.gov (United States)

    Fitzgerald, G A; Yang, G; Paschos, G K; Liang, X; Skarke, C

    2015-09-01

    Molecular clockworks knit together diverse biological networks and compelling evidence from model systems infers their importance in metabolism, immunological and cardiovascular function. Despite this and the diurnal variation in many aspects of human physiology and the phenotypic expression of disease, our understanding of the role and importance of clock function and dysfunction in humans is modest. There are tantalizing hints of connection across the translational divide and some correlative evidence of gene variation and human disease but most of what we know derives from forced desynchrony protocols in controlled environments. We now have the ability to monitor quantitatively ex vivo or in vivo the genome, metabolome, proteome and microbiome of humans in the wild. Combining this capability, with the power of mobile telephony and the evolution of remote sensing, affords a new opportunity for deep phenotyping, including the characterization of diurnal behaviour and the assessment of the impact of the clock on approved drug function.

  14. Human Metabolic Enzymes Deficiency: A Genetic Mutation Based Approach

    Science.gov (United States)

    Chaturvedi, Swati; Singh, Ashok K.; Maity, Siddhartha; Sarkar, Srimanta

    2016-01-01

    One of the extreme challenges in biology is to ameliorate the understanding of the mechanisms which emphasize metabolic enzyme deficiency (MED) and how these pretend to have influence on human health. However, it has been manifested that MED could be either inherited as inborn error of metabolism (IEM) or acquired, which carries a high risk of interrupted biochemical reactions. Enzyme deficiency results in accumulation of toxic compounds that may disrupt normal organ functions and cause failure in producing crucial biological compounds and other intermediates. The MED related disorders cover widespread clinical presentations and can involve almost any organ system. To sum up the causal factors of almost all the MED-associated disorders, we decided to embark on a less traveled but nonetheless relevant direction, by focusing our attention on associated gene family products, regulation of their expression, genetic mutation, and mutation types. In addition, the review also outlines the clinical presentations as well as diagnostic and therapeutic approaches. PMID:27051561

  15. Thyroid hormone metabolism and the developing human lung.

    Science.gov (United States)

    Hume, R; Richard, K; Kaptein, E; Stanley, E L; Visser, T J; Coughtrie, M W

    2001-05-01

    Thyroid hormones are involved in the regulation of fetal lung development, and maturation is accelerated in animal models by antepartum exposure to raised concentrations of the receptor-active thyroid hormone triiodothyronine and glucocorticoids. It is essential that the nature of the regulation of the spatial and temporal metabolism of iodothyronines in the human fetus and infant is known before effective therapies can be developed to modify human lung maturation. Thyroid hormone bioavailability to the human fetus is regulated in part by enzymatic deiodination and reversible sulfation of iodothyronines, with contributions from other factors such as fetomaternal and fetoamniotic hormone transfers, fetal thyroid gland production, and the activities of plasma membrane transporters mediating uptake of iodothyronines from plasma into tissues. Copyright 2001 S. Karger AG, Basel.

  16. "Bridge Proteins" Link Inflammation and Metabolic Diseases: Potential Targets for Therapeutics.

    Science.gov (United States)

    Jiang, Hailong; Qin, Guixin; Zhang, Xuefeng; Che, Dongsheng

    2016-06-26

    Clinical observations support the postulate that chronic low-grade inflammation underlies metabolic diseases and inflammatory mediators can trigger some metabolic diseases. In disorder condition, what is the first one: metabolic diseases cause inflammation or conversely? This "chicken or egg" type question was hard to answer. However, instead of focusing on this difficult issue, we should ask another challenging question: what are the links between inflammation and metabolic diseases? Seizing the key from this chaos may be the best way to solve the problem and break the cycle. To answer this question, we review the regulators (such as NF-κB, PPARs, mTOR, and STAT3) that have important roles in both metabolism and inflammation. These "bridge proteins" that link metabolic diseases and inflammation not only increase our understanding of these two diseases, but also provide potential targets for therapeutics and practical clinical applications.

  17. Founders lecture 2007. Metabolic bone disease: what has changed in 30 years?

    Energy Technology Data Exchange (ETDEWEB)

    Sundaram, Murali [Cleveland Clinic, Diagnostic Radiology, MSK, Cleveland, OH (United States)

    2009-09-15

    To provide an update on imaging of metabolic bone disease based on new developments, findings, and changing practices over the past 30 years. Literature review of osteoporosis, osteomalacia, renal osteodystrophy, Paget's disease, bisphosphonates, with an emphasis on imaging. Cited references and pertinent findings. Significant developments have occurred in the imaging of metabolic bone disease over the past 30 years. (orig.)

  18. The meaning of aluminium exposure on human health and aluminium-related diseases.

    Science.gov (United States)

    Crisponi, Guido; Fanni, Daniela; Gerosa, Clara; Nemolato, Sonia; Nurchi, Valeria M; Crespo-Alonso, Miriam; Lachowicz, Joanna I; Faa, Gavino

    2013-02-01

    The aim of this review is to attempt to answer extremely important questions related to aluminium-related diseases. Starting from an overview on the main sources of aluminium exposure in everyday life, the principal aspects of aluminium metabolism in humans have been taken into consideration in an attempt to enlighten the main metabolic pathways utilised by trivalent metal ions in different organs. The second part of this review is focused on the available evidence concerning the pathogenetic consequences of aluminium overload in human health, with particular attention to its putative role in bone and neurodegenerative human diseases.

  19. Reduced penetrance in human inherited disease

    African Journals Online (AJOL)

    Rabah M. Shawky

    2014-01-31

    Jan 31, 2014 ... tant role in cellular senescence, tumorigenesis and in several diseases ... A correlation between epigenetic DNA modifications and human life span ... Most studies demonstrated that aging is associated with a relaxation in ...

  20. Intestinal SGLT1 in metabolic health and disease.

    Science.gov (United States)

    Lehmann, Anders; Hornby, Pamela J

    2016-06-01

    The Na(+)-glucose cotransporter 1 (SGLT1/SLC5A1) is predominantly expressed in the small intestine. It transports glucose and galactose across the apical membrane in a process driven by a Na(+) gradient created by Na(+)-K(+)-ATPase. SGLT2 is the major form found in the kidney, and SGLT2-selective inhibitors are a new class of treatment for type 2 diabetes mellitus (T2DM). Recent data from patients treated with dual SGLT1/2 inhibitors or SGLT2-selective drugs such as canagliflozin (SGLT1 IC50 = 663 nM) warrant evaluation of SGLT1 inhibition for T2DM. SGLT1 activity is highly dynamic, with modulation by multiple mechanisms to ensure maximal uptake of carbohydrates (CHOs). Intestinal SGLT1 inhibition lowers and delays the glucose excursion following CHO ingestion and augments glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion. The latter is likely due to increased glucose exposure of the colonic microbiota and formation of metabolites such as L cell secretagogues. GLP-1 and PYY secretion suppresses food intake, enhances the ileal brake, and has an incretin effect. An increase in colonic microbial production of propionate could contribute to intestinal gluconeogenesis and mediate positive metabolic effects. On the other hand, a threshold of SGLT1 inhibition that could lead to gastrointestinal intolerability is unclear. Altered Na(+) homeostasis and increased colonic CHO may result in diarrhea and adverse gastrointestinal effects. This review considers the potential mechanisms contributing to positive metabolic and negative intestinal effects. Compounds that inhibit SGLT1 must balance the modulation of these mechanisms to achieve therapeutic efficacy for metabolic diseases. Copyright © 2016 the American Physiological Society.

  1. Tissue Renin-Angiotensin Systems: A Unifying Hypothesis of Metabolic Disease

    DEFF Research Database (Denmark)

    Skov, Jeppe; Persson, Frederik; Frøkiær, Jørgen

    2014-01-01

    The actions of angiotensin peptides are diverse and locally acting tissue renin-angiotensin systems (RAS) are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g., diabetes) and its complications and blockers of RAS have been demonstrated to p...... disease initiate and progress. The hypothesis plausibly unifies the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control....

  2. Understanding Postprandial Inflammation and Its Relationship to Lifestyle Behaviour and Metabolic Diseases

    Directory of Open Access Journals (Sweden)

    Boudewijn Klop

    2012-01-01

    Full Text Available Postprandial hyperlipidemia with accumulation of remnant lipoproteins is a common metabolic disturbance associated with atherosclerosis and vascular dysfunction, particularly during chronic disease states such as obesity, the metabolic syndrome and, diabetes. Remnant lipoproteins become attached to the vascular wall, where they can penetrate intact endothelium causing foam cell formation. Postprandial remnant lipoproteins can activate circulating leukocytes, upregulate the expression of endothelial adhesion molecules, facilitate adhesion and migration of inflammatory cells into the subendothelial space, and activate the complement system. Since humans are postprandial most of the day, the continuous generation of remnants after each meal may be one of the triggers for the development of atherosclerosis. Modulation of postprandial lipemia by lifestyle changes and pharmacological interventions could result in a further decrease of cardiovascular mortality and morbidity. This paper will provide an update on current concepts concerning the relationship between postprandial lipemia, inflammation, vascular function, and therapeutic options.

  3. Proteome analysis of human substantia nigra in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Werner Cornelius J

    2008-02-01

    Full Text Available Abstract Background Parkinson's disease (PD is the most common neurodegenerative disorder involving the motor system. Although not being the only region involved in PD, affection of the substantia nigra and its projections is responsible for some of the most debilitating features of the disease. To further advance a comprehensive understanding of nigral pathology, we conducted a tissue based comparative proteome study of healthy and diseased human substantia nigra. Results The gross number of differentially regulated proteins in PD was 221. In total, we identified 37 proteins, of which 16 were differentially expressed. Identified differential proteins comprised elements of iron metabolism (H-ferritin and glutathione-related redox metabolism (GST M3, GST P1, GST O1, including novel redox proteins (SH3BGRL. Additionally, many glial or related proteins were found to be differentially regulated in PD (GFAP, GMFB, galectin-1, sorcin, as well as proteins belonging to metabolic pathways sparsely described in PD, such as adenosyl homocysteinase (methylation, aldehyde dehydrogenase 1 and cellular retinol-binding protein 1 (aldehyde metabolism. Further differentially regulated proteins included annexin V, beta-tubulin cofactor A, coactosin-like protein and V-type ATPase subunit 1. Proteins that were similarly expressed in healthy or diseased substantia nigra comprised housekeeping proteins such as COX5A, Rho GDI alpha, actin gamma 1, creatin-kinase B, lactate dehydrogenase B, disulfide isomerase ER-60, Rab GDI beta, methyl glyoxalase 1 (AGE metabolism and glutamine synthetase. Interestingly, also DJ-1 and UCH-L1 were expressed similarly. Furthermore, proteins believed to serve as internal standards were found to be expressed in a constant manner, such as 14-3-3 epsilon and hCRMP-2, thus lending further validity to our results. Conclusion Using an approach encompassing high sensitivity and high resolution, we show that alterations of SN in PD include many

  4. Prevalence of chronic kidney disease in adults with metabolic syndrome

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    P C Emem-Chioma

    2011-01-01

    Full Text Available The burden of chronic kidney disease (CKD and other non- communicable diseases continues to rise globally, and recent studies suggest that metabolic syndrome (MS may add to this burden by contributing to the development of CKD. Given that reports on the prevalence of CKD in patients with MS in this environment are scanty, this study was undertaken with the sole aim of determining the prevalence of CKD in subjects with MS as defined by the International Diabetes Federation (IDF and the National Cholesterol Education Project Adult Treatment Panel III (NCEP ATP III. A total of 240 consenting adults (18-70 years attending the general out- patient clinic of the General Hospital Okrika for various ailments were studied. Subjects were screened for MS as per the above- mentioned criteria. Estimated GFR (eGFR was determined with Modification of Diet for Renal Disease (MDRD formula and CKD was defined as eGFR less than 60 mL/min/1.73 m2 . Data was analyzed using SPSS version 12.0 and Epi info version 4.06d; P 0.05. CKD was more common in subjects with MS compared with those without, although the difference was not statistically significant. The prevalence of CKD in subjects with MS in our study population did not differ significantly when the different MS definitions were employed.

  5. Microvesicles and exosomes: new players in metabolic and cardiovascular disease.

    Science.gov (United States)

    Lawson, Charlotte; Vicencio, Jose M; Yellon, Derek M; Davidson, Sean M

    2016-02-01

    The past decade has witnessed an exponential increase in the number of publications referring to extracellular vesicles (EVs). For many years considered to be extracellular debris, EVs are now seen as novel mediators of endocrine signalling via cell-to-cell communication. With the capability of transferring proteins and nucleic acids from one cell to another, they have become an attractive focus of research for different pathological settings and are now regarded as both mediators and biomarkers of disease including cardio-metabolic disease. They also offer therapeutic potential as signalling agents capable of targeting tissues or cells with specific peptides or miRNAs. In this review, we focus on the role that microvesicles (MVs) and exosomes, the two most studied classes of EV, have in diabetes, cardiovascular disease, endothelial dysfunction, coagulopathies, and polycystic ovary syndrome. We also provide an overview of current developments in MV/exosome isolation techniques from plasma and other fluids, comparing different available commercial and non-commercial methods. We describe different techniques for their optical/biochemical characterization and quantitation. We also review the signalling pathways that exosomes and MVs activate in target cells and provide some insight into their use as biomarkers or potential therapeutic agents. In summary, we give an updated focus on the role that these exciting novel nanoparticles offer for the endocrine community.

  6. Intestinal and hepatic metabolism of glutamine and citrulline in humans.

    Science.gov (United States)

    van de Poll, Marcel C G; Ligthart-Melis, Gerdien C; Boelens, Petra G; Deutz, Nicolaas E P; van Leeuwen, Paul A M; Dejong, Cornelis H C

    2007-06-01

    Glutamine plays an important role in nitrogen homeostasis and intestinal substrate supply. It has been suggested that glutamine is a precursor for arginine through an intestinal-renal pathway involving inter-organ transport of citrulline. The importance of intestinal glutamine metabolism for endogenous arginine synthesis in humans, however, has remained unaddressed. The aim of this study was to investigate the intestinal conversion of glutamine to citrulline and the effect of the liver on splanchnic citrulline metabolism in humans. Eight patients undergoing upper gastrointestinal surgery received a primed continuous intravenous infusion of [2-(15)N]glutamine and [ureido-(13)C-(2)H(2)]citrulline. Arterial, portal venous and hepatic venous blood were sampled and portal and hepatic blood flows were measured. Organ specific amino acid uptake (disposal), production and net balance, as well as whole body rates of plasma appearance were calculated according to established methods. The intestines consumed glutamine at a rate that was dependent on glutamine supply. Approximately 13% of glutamine taken up by the intestines was converted to citrulline. Quantitatively glutamine was the only important precursor for intestinal citrulline release. Both glutamine and citrulline were consumed and produced by the liver, but net hepatic flux of both amino acids was not significantly different from zero. Plasma glutamine was the precursor of 80% of plasma citrulline and plasma citrulline in turn was the precursor of 10% of plasma arginine. In conclusion, glutamine is an important precursor for the synthesis of arginine after intestinal conversion to citrulline in humans.

  7. Lysosome/lipid droplet interplay in metabolic diseases.

    Science.gov (United States)

    Dugail, Isabelle

    2014-01-01

    Lysosomes and lipid droplets are generally considered as intracellular compartments with divergent roles in cell metabolism, lipid droplets serving as lipid reservoirs in anabolic pathways, whereas lysosomes are specialized in the catabolism of intracellular components. During the last few years, new insights in the biology of lysosomes has challenged this view by providing evidence for the importance of lysosome recycling as a sparing mechanism to maintain cellular fitness. On the other hand the understanding of lipid droplets has evolved from an inert intracellular deposit toward the status of an intracellular organelle with dynamic roles in cellular homeostasis beyond storage. These unrelated aspects have also recently converged in the finding of unexpected lipid droplet/lysosome communication through autophagy, and the discovery of lysosome-mediated lipid droplet degradation called lipopagy. Furthermore, adipocytes which are professional cells for lipid droplet formation were also shown to be active in peptide antigen presentation a pathway requiring lysosomal activity. The potential importance of lipid droplet/lysosome interplay is discussed in the context of metabolic diseases and the setting of chronic inflammation.

  8. Obesity and metabolic syndrome as related to cardiovascular disease.

    Science.gov (United States)

    Nikolopoulou, Angeliki; Kadoglou, Nikolaos P E

    2012-07-01

    The metabolic syndrome (MetS) constitutes a multifaceted disorder, including obesity, dyslipidemia, hyperglycemia and hypertension, associated with an increased propensity towards cardiovascular disease (CVD). Besides this, accumulating data suggest the involvement of nontraditional, novel, cardiovascular risk factors in MetS. Among them, insulin resistance seems to possess a predominant role in MetS-related CVD in obese patients. Furthermore, adipose tissue fatty acid metabolism, increased incidence of oxidative stress and endothelial dysfunction, and excessive production of adipocyte derivatives, known as adipokines, have all been proposed to contribute to the pathogenesis of CVD in obese patients with MetS. Lifestyle interventions, such as weight loss and increased physical activity, have long been the cornerstone for the treatment of obesity-related disorders. With the exception of obesity, pharmaceutical interventions targeting each disorder of MetS have yielded considerable improvement in cardiovascular morbidity and mortality. The long-term management of obesity and its complications seems promising but requires further investigation.

  9. Protein Misfolding and Human Disease

    DEFF Research Database (Denmark)

    Gregersen, Niels; Bross, Peter Gerd; Vang, Søren

    2006-01-01

    phenylketonuria, Parkinson's disease, α-1-antitrypsin deficiency, familial neurohypophyseal diabetes insipidus, and short-chain acyl-CoA dehydrogenase deficiency. Despite the differences, an emerging paradigm suggests that the cellular effects of protein misfolding provide a common framework that may contribute......Protein misfolding is a common event in living cells. In young and healthy cells, the misfolded protein load is disposed of by protein quality control (PQC) systems. In aging cells and in cells from certain individuals with genetic diseases, the load may overwhelm the PQC capacity, resulting...... in accumulation of misfolded proteins. Dependent on the properties of the protein and the efficiency of the PQC systems, the accumulated protein may be degraded or assembled into toxic oligomers and aggregates. To illustrate this concept, we discuss a number of very different protein misfolding diseases including...

  10. Hepcidin: an important iron metabolism regulator in chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Sandra Azevedo Antunes

    Full Text Available Abstract Anemia is a common complication and its impact on morbimortality in patients with chronic kidney disease (CKD is well known. The discovery of hepcidin and its functions has contributed to a better understanding of iron metabolism disorders in CKD anemia. Hepcidin is a peptide mainly produced by hepatocytes and, through a connection with ferroportin, it regulates iron absorption in the duodenum and its release of stock cells. High hepcidin concentrations described in patients with CKD, especially in more advanced stages are attributed to decreased renal excretion and increased production. The elevation of hepcidin has been associated with infection, inflammation, atherosclerosis, insulin resistance and oxidative stress. Some strategies were tested to reduce the effects of hepcidin in patients with CKD, however more studies are necessary to assess the impact of its modulation in the management of anemia in this population.

  11. Metabolic bone disease in juvenile koalas (Phascolartcos cinereus).

    Science.gov (United States)

    Pye, Geoffrey W; Gait, Sarah Catherine; Mulot, Baptiste; de Asua, Maria Delclaux Real; Martinez-Nevado, Eva; Bonar, Christopher J; Baines, Stephen J; Baines, Elizabeth A

    2013-06-01

    Due to climate restrictions in parts of North America and Europe, koalas (Phascolarctos cinereus) are housed indoors. Koala young (joeys) raised indoors are susceptible to the development of metabolic bone disease (MBD) due to a lack of exposure to natural ultraviolet light to themselves and their female parents (dams). In this retrospective study, radiographs from 27 koala joeys born at four zoos in North America and two zoos in Europe were evaluated for signs of MBD. Eight of the joeys were radiographically diagnosed with MBD and four additional joeys were considered suspect MBD cases; in two joeys absence or presence of MBD could not be determined. All joeys had mild to severe hip and shoulder dysplasia. There were significant associations between a lack of exposure to UV light and MBD development and between MBD and the degree of severity of hip and shoulder dysplasia. It is recommended to house breeding female koalas and their joeys outdoors whenever possible.

  12. ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism.

    Science.gov (United States)

    Peters, Heidi; Buck, Nicole; Wanders, Ronald; Ruiter, Jos; Waterham, Hans; Koster, Janet; Yaplito-Lee, Joy; Ferdinandusse, Sacha; Pitt, James

    2014-11-01

    Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this diagnosis was excluded by HIBCH sequencing and normal enzyme activity. In contrast to HIBCH deficiency, the excretion of 3-hydroxyisobutyryl-carnitine was normal in the children, suggesting deficiency of short-chain enoyl-CoA hydratase (ECHS1 gene). This mitochondrial enzyme is active in several metabolic pathways involving fatty acids and amino acids, including valine, and is immediately upstream of HIBCH in the valine pathway. Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1. ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity. The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders. Deficiency of ECHS1 or HIBCH should be considered in children with Leigh disease. Urine metabolite testing can detect and distinguish between these two disorders.

  13. Human Metabolism and Interactions of Deployment-Related Chemicals

    Science.gov (United States)

    2008-08-01

    consisted of the pGL3- CYP3A4, pCDG1-SXR, and pRL-TK plasmids in the amounts of 360, 90, and 10 ng, respectively, along with 540 ng sonicated salmon sperm...oxidative stress in rat brain and liver is prevented by vitamin E or allopurinol. Toxicol. Lett. 2001; 118: 139-146. 34. Li, P., Nijhawan, D...acids, eicosanoids, fat- soluble vitamins /1/. Among fifty-seven CYP isoforms known in humans, fifteen are involved in the metabolism of

  14. [Disorders of carbohydrate metabolism, dyslipidemia, and bone metabolic disease after hematopoietic stem cell transplantation].

    Science.gov (United States)

    Wędrychowicz, Anna; Starzykk, Jerzy

    2013-01-01

    Among long-term survivors after hematopoietic stem cell transplantation (HSCT) late endocrine complications are observed in 20-50%. Very often these complications influence significantly the patient´s life and have to be treated till the end of life. Their proper prevention and monitoring are extremely important in patients who underwent HSCT during childhood. Since the 90s of the last millennium/century, thyroid dysfunction, disorders of somatic and sexual development, and disturbances of fertility have been presented in several publications. In the paper, less known endocrine complications after HSCT published in the last years are discussed. Disorders of carbohydrate metabolism, post-transplant diabetes and insulin resistance are presented. Moreover, dyslipidemia, hypertension, and post-transplant bone metabolic disease are demonstrated/shown. The paper describes the etiopathogenesis, methods of prevention as well as treatment and the results of the treatment of these endocrine complications after HSCT. Moreover, actual recommendations for screening and prevention of endocrine complications in long-term HCT survivors are presented.

  15. Physiochemical basis of human degenerative disease

    Directory of Open Access Journals (Sweden)

    Zeliger Harold I.

    2015-03-01

    Full Text Available The onset of human degenerative diseases in humans, including type 2 diabetes, cardiovascular disease, neurological disorders, neurodevelopmental disease and neurodegenerative disease has been shown to be related to exposures to persistent organic pollutants, including polychlorinated biphenyls, chlorinated pesticides, polybrominated diphenyl ethers and others, as well as to polynuclear aromatic hydrocarbons, phthalates, bisphenol-A and other aromatic lipophilic species. The onset of these diseases has also been related to exposures to transition metal ions. A physiochemical mechanism for the onset of degenerative environmental disease dependent upon exposure to a combination of lipophilic aromatic hydrocarbons and transition metal ions is proposed here. The findings reported here also, for the first time, explain why aromatic hydrocarbons exhibit greater toxicity than aliphatic hydrocarbons of equal carbon numbers.

  16. Endocrine and metabolic disease: Confocal microscopy as a diagnostic aid

    Directory of Open Access Journals (Sweden)

    Jaikrit Bhutani

    2015-01-01

    Full Text Available Diabetes is a systemic disease associated with many complications. These can be prevented and managed effectively if detected promptly. Confocal microscopy (CFM is a diagnostic tool which has the potential to help in early detection of disease and timely management. CFM has the potential to serve as an excellent noninvasive modality for in vivo imaging and morphological analysis, which can aid us in assessing and monitoring various infectious and pathological diseases at the cellular level. Besides ophthalmological indications, CFM has shown good sensitivity and specificity for identifying those at risk of neuropathy and foot ulceration, monitoring evolution and therapeutic response in a wide range of neuropathies apart from diabetic neuropathy. Through this communication, we aim to sensitize the endocrinologists towards cerebral cavernous malformation as a biomarker to evaluate potential outcomes and therapies in human diabetic neuropathy.

  17. Persistent Organic Pollutants and Concern Over the Link with Insulin Resistance Related Metabolic Diseases.

    Science.gov (United States)

    Mostafalou, Sara

    Persistent organic pollutants (POPs) are mostly halogenated compounds tending to persist in the environment, enter into the food chain, and accumulate in fat mass of mammals due to their high lipophilicity. They include some organochlorine pesticides, polychlorinated biphenyls, brominated flame retardants and polycyclic aromatic hydrocarbons. Some of these chemicals were widely used in the past so that their residues can be detected in the human body, though their usage has been banned for years. POPs have been shown to perturb the health of biological systems in different ways evidenced by carcinogenicity and disrupting effects on endocrine, immune, and reproductive systems. There are many epidemiologic and experimental studies on the association of exposure to POPs with insulin resistance and related metabolic disorders like obesity, diabetes, and metabolic syndrome. Inflammation as a known mechanism accompanying insulin resistance has also been shown to arise in insulin target tissues exposed to POPs. This review addresses the breast milk concentration of POPs in different regions of the world, synthesizes the current information on the association of POPs with insulin resistance related metabolic disorders, and discusses the inflammation as an involved mechanism. Considering high prevalence of insulin resistance related metabolic diseases and their relation with POPs, much need is felt regarding international and regional programs to not only limit their production and usage but eliminate these persistent pollutants from the environment.

  18. Human Echinococcosis: A Neglected Disease

    Directory of Open Access Journals (Sweden)

    António Menezes da Silva

    2010-01-01

    Full Text Available Echinococcosis is among the most neglected parasitic diseases. Development of new drugs and other treatment modalities receives very little attention, if any. In most developed countries, Cystic Echinococcosis (CE is an imported disease of very low incidence and prevalence and is found almost exclusively in migrants from endemic regions. In endemic regions, predominantly settings with limited resources, patient numbers are high. Whole communities do not have access to appropriate treatment. The choice of treatment modalities is limited because of poor infrastructure and shortage of equipment and drugs. In this context, CE meets the criteria for a neglected disease. Furthermore, the terminology related to the designations around the parasite, its evolution and some therapeutic procedures is not uniform and sometimes inappropriate terms and wrong designations are used based on incorrect concepts. Although all of us know the different aspects of the disease it is pertinent to remember some important points and, above all, to clarify some aspects concerning the hydatid cyst's nomenclature in order to understand better the therapeutic options in the liver locations, particularly the different surgical approaches.

  19. mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases.

    Science.gov (United States)

    Yang, Z; Ming, X-F

    2012-12-01

    The continuing increase in the prevalence of obesity and metabolic disorders such as type-II diabetes and an accelerating aging population globally will remain the major contributors to cardiovascular mortality and morbidity in the 21st century. It is well known that aging is highly associated with metabolic and cardiovascular diseases. Growing evidence also shows that obesity and metabolic diseases accelerate aging process. Studies in experimental animal models demonstrate similarity of metabolic and cardiovascular phenotypes in metabolic diseases and old age, e.g. insulin resistance, oxidative stress, chronic low grade inflammation, cardiac hypertrophy, cardiac fibrosis, and heart failure, as well as vascular dysfunctions. Despite intensive research, the molecular mechanisms linking metabolic stress, aging, and ultimately cardiovascular diseases are still elusive. Although the mammalian target of rapamycin (mTOR) signalling is a well known regulator of metabolism and lifespan in model organisms, its central role in linking metabolic stress, aging and cardiovascular diseases is recently emerging. In this article, we review the evidence supporting the role of mTOR signalling as a molecular interface connecting metabolic stress, aging and cardiovascular diseases. The therapeutic potentials of targeting mTOR signalling to protect against metabolic and age-associated cardiovascular diseases are discussed. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity.

  20. Molecular Pathology of Human Prion Diseases

    Directory of Open Access Journals (Sweden)

    2009-03-01

    Full Text Available Prion diseases are fatal neurodegenerative conditions in humans and animals. In this review, we summarize the molecular background of phenotypic variability, relation of prion protein (PrP to other proteins associated with neurodegenerative diseases, and pathogenesis of neuronal vulnerability. PrP exists in different forms that may be present in both diseased and non-diseased brain, however, abundant disease-associated PrP together with tissue pathology characterizes prion diseases and associates with transmissibility. Prion diseases have different etiological background with distinct pathogenesis and phenotype. Mutations of the prion protein gene are associated with genetic forms. The codon 129 polymorphism in combination with the Western blot pattern of PrP after proteinase K digestion serves as a basis for molecular subtyping of sporadic Creutzfeldt-Jakob disease. Tissue damage may result from several parallel, interacting or subsequent pathways that involve cellular systems associated with synapses, protein processing, oxidative stress, autophagy, and apoptosis.

  1. [Primary human demodicosis. A disease sui generis].

    Science.gov (United States)

    Hsu, C-K; Zink, A; Wei, K-J; Dzika, E; Plewig, G; Chen, W

    2015-03-01

    Human Demodex mites (Demodex folliculorum and Demodex brevis) are unique in that they are an obligate human ectoparasite that can inhabit the pilosebaceous unit lifelong without causing obvious host immune response in most cases. The mode of symbiosis between humans and human Demodex mites is unclear, while the pathogenicity of human Demodex mites in many inflammatory skin diseases is now better understood. Primary human demodicosis is a skin disease sui generis not associated with local or systemic immunosuppression. Diagnosis is often underestimated and differentiation from folliculitis, papulopustular rosacea and perioral dermatitis is not always straightforward. Dependent on the morphology and degree of inflammation, the clinical manifestations can be classified into spinulate, papulopustular, nodulocystic, crustic and fulminant demodicosis. Therapy success can be achieved only with acaricides/arachidicides. The effective doses, optimal regimen and antimicrobial resistance remain to be determined.

  2. Global biogeography of human infectious diseases.

    Science.gov (United States)

    Murray, Kris A; Preston, Nicholas; Allen, Toph; Zambrana-Torrelio, Carlos; Hosseini, Parviez R; Daszak, Peter

    2015-10-13

    The distributions of most infectious agents causing disease in humans are poorly resolved or unknown. However, poorly known and unknown agents contribute to the global burden of disease and will underlie many future disease risks. Existing patterns of infectious disease co-occurrence could thus play a critical role in resolving or anticipating current and future disease threats. We analyzed the global occurrence patterns of 187 human infectious diseases across 225 countries and seven epidemiological classes (human-specific, zoonotic, vector-borne, non-vector-borne, bacterial, viral, and parasitic) to show that human infectious diseases exhibit distinct spatial grouping patterns at a global scale. We demonstrate, using outbreaks of Ebola virus as a test case, that this spatial structuring provides an untapped source of prior information that could be used to tighten the focus of a range of health-related research and management activities at early stages or in data-poor settings, including disease surveillance, outbreak responses, or optimizing pathogen discovery. In examining the correlates of these spatial patterns, among a range of geographic, epidemiological, environmental, and social factors, mammalian biodiversity was the strongest predictor of infectious disease co-occurrence overall and for six of the seven disease classes examined, giving rise to a striking congruence between global pathogeographic and "Wallacean" zoogeographic patterns. This clear biogeographic signal suggests that infectious disease assemblages remain fundamentally constrained in their distributions by ecological barriers to dispersal or establishment, despite the homogenizing forces of globalization. Pathogeography thus provides an overarching context in which other factors promoting infectious disease emergence and spread are set.

  3. Metabolic Syndrome: An Important Risk Factor for Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Pei Zhang

    2014-01-01

    Full Text Available Metabolic syndrome is becoming commoner due to a rise in obesity rates among adults. Generally speaking, a person with metabolic syndrome is twice as likely to develop cardiovascular disease and five times as likely to develop diabetes as someone without metabolic syndrome. Increasing oxidative stress in metabolic syndrome and Parkinson’s disease is mentioned in the comprehensive articles; however, the system review about clear relation between metabolic syndrome and Parkinson’s disease is deficient. In this review, we will focus on the analysis that the metabolic syndrome may be a risk factor for Parkinson’s disease and the preventions that reduce the incident of Parkinson’s disease by regulating the oxidative stress.

  4. Glycerol: An unexpected major metabolite of energy metabolism by the human malaria parasite

    Directory of Open Access Journals (Sweden)

    Bray Patrick G

    2009-03-01

    Full Text Available Abstract Background Malaria is a global health emergency, and yet our understanding of the energy metabolism of the principle causative agent of this devastating disease, Plasmodium falciparum, remains rather basic. Glucose was shown to be an essential nutritional requirement nearly 100 years ago and since this original observation, much of the current knowledge of Plasmodium energy metabolism is based on early biochemical work, performed using basic analytical techniques (e.g. paper chromatography, carried out almost exclusively on avian and rodent malaria. Data derived from malaria parasite genome and transcriptome studies suggest that the energy metabolism of the parasite may be more complex than hitherto anticipated. This study was undertaken in order to further characterize the fate of glucose catabolism in the human malaria parasite, P. falciparum. Methods Products of glucose catabolism were determined by incubating erythrocyte-freed parasites with D-[1-13C] glucose under controlled conditions and metabolites were identified using 13C-NMR spectroscopy. Results Following a 2 h incubation of freed-P. falciparum parasites with 25 mM D-[1-13C] glucose (n = 4, the major metabolites identified included; [3-13C] lactate, [1,3-13C] glycerol, [3-13C] pyruvate, [3-13C] alanine and [3-13C] glycerol-3-phosphate. Control experiments performed with uninfected erythrocytes incubated under identical conditions did not show any metabolism of D-[1-13C] glucose to glycerol or glycerol-3-phosphate. Discussion The identification of glycerol as a major glucose metabolite confirms the view that energy metabolism in this parasite is more complex than previously proposed. It is hypothesized here that glycerol production by the malaria parasite is the result of a metabolic adaptation to growth in O2-limited (and CO2 elevated conditions by the operation of a glycerol-3-phosphate shuttle for the re-oxidation of assimilatory NADH. Similar metabolic adaptations have

  5. Mitochondrial protein import and human health and disease.

    Science.gov (United States)

    MacKenzie, James A; Payne, R Mark

    2007-05-01

    The targeting and assembly of nuclear-encoded mitochondrial proteins are essential processes because the energy supply of humans is dependent upon the proper functioning of mitochondria. Defective import of mitochondrial proteins can arise from mutations in the targeting signals within precursor proteins, from mutations that disrupt the proper functioning of the import machinery, or from deficiencies in the chaperones involved in the proper folding and assembly of proteins once they are imported. Defects in these steps of import have been shown to lead to oxidative stress, neurodegenerative diseases, and metabolic disorders. In addition, protein import into mitochondria has been found to be a dynamically regulated process that varies in response to conditions such as oxidative stress, aging, drug treatment, and exercise. This review focuses on how mitochondrial protein import affects human health and disease.

  6. PXR- and CAR-mediated herbal effect on human diseases.

    Science.gov (United States)

    Xu, Chenshu; Huang, Min; Bi, Huichang

    2016-09-01

    The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two members of the nuclear receptor superfamily that regulate a broad range of genes involved in drug metabolism and transport. A variety of naturally occurring compounds present in herbal medicines were identified as ligands of PXR and CAR. Recently, accumulative evidences have revealed the PXR- and CAR-mediated herbal effect against multiple human diseases, including inflammatory bowel disease (IBD), cholestatic liver disease, and jaundice. The current review summarized the recent progress in identifying the expanding libraries of herbal medicine as ligands for PXR and CAR. Moreover, the potential for herbal medicines as promising therapeutic agents which were mainly regulated through PXR/CAR signaling pathways was also discussed. The discovery of herbal medicines as modulators of PXR and CAR, and their PXR- and CAR-mediated effect on human diseases will provide a basis for rational drug design, and eventually be explored as a novel therapeutic approach against human diseases. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

  7. Maternal perinatal undernutrition modifies lactose and serotranferrin in milk: relevance to the programming of metabolic diseases?

    Science.gov (United States)

    Wattez, J S; Delmont, A; Bouvet, M; Beseme, O; Goers, S; Delahaye, F; Laborie, C; Lesage, J; Foligné, B; Breton, C; Metges, C C; Vieau, D; Pinet, F

    2015-03-01

    A close link between intrauterine growth restriction and development of chronic adult diseases such as obesity, diabetes, and hypertension has been established both in humans and animals. Modification of growth velocity during the early postnatal period (i.e., lactation) may also sensitize to the development of metabolic syndrome in adulthood. This suggests that milk composition may have long-lasting programming/deprogramming metabolic effects in the offspring. We therefore assess the effects of maternal perinatal denutrition on breast milk composition in a food-restricted 50% (FR50) rat model. Monosaccharides and fatty acids were characterized by gas chromatography, and proteins were profiled by surface-enhanced laser desorption/ionization-time-of-flight analysis in milk samples from FR50 and control rat dams. Milk analysis of FR50 rats demonstrated that maternal undernutrition decreases lactose concentration and modulates lipid profile at postnatal day 10 by increasing the unsaturated fatty acids/saturated fatty acids and diminishes serotransferrin levels at postnatal day 21. Our data indicate that maternal perinatal undernutrition modifies milk composition both quantitatively and qualitatively. These modifications by maternal nutrition open new perspectives to identify molecules that could be used in artificial milk to protect from the subsequent development of metabolic diseases.

  8. Vitamin B12: one carbon metabolism, fetal growth and programming for chronic disease.

    Science.gov (United States)

    Rush, E C; Katre, P; Yajnik, C S

    2014-01-01

    This review brings together human and animal studies and reviews that examine the possible role of maternal vitamin B12 (B12) on fetal growth and its programming for susceptibility to chronic disease. A selective literature review was undertaken to identify studies and reviews that investigate these issues, particularly in the context of a vegetarian diet that may be low in B12 and protein and high in carbohydrate. Evidence is accumulating that maternal B12 status influences fetal growth and development. Low maternal vitamin B12 status and protein intake are associated with increased risk of neural tube defect, low lean mass and excess adiposity, increased insulin resistance, impaired neurodevelopment and altered risk of cancer in the offspring. Vitamin B12 is a key nutrient associated with one carbon metabolic pathways related to substrate metabolism, synthesis and stability of nucleic acids and methylation of DNA which regulates gene expression. Understanding of factors regulating maternal-fetal one carbon metabolism and its role in fetal programming of non communicable diseases could help design effective interventions, starting with maternal nutrition before conception.

  9. Metabolomics Analysis of Metabolic Effects of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibition on Human Cancer Cells

    Science.gov (United States)

    Tolstikov, Vladimir; Nikolayev, Alexander; Dong, Sucai; Zhao, Genshi; Kuo, Ming-Shang

    2014-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) plays an important role in cellular bioenergetics. It is responsible for converting nicotinamide to nicotinamide adenine dinucleotide, an essential molecule in cellular metabolism. NAMPT has been extensively studied over the past decade due to its role as a key regulator of nicotinamide adenine dinucleotide–consuming enzymes. NAMPT is also known as a potential target for therapeutic intervention due to its involvement in disease. In the current study, we used a global mass spectrometry–based metabolomic approach to investigate the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on metabolic perturbations in human cancer cells. We treated A2780 (ovarian cancer) and HCT-116 (colorectal cancer) cell lines with FK866 in the presence and absence of nicotinic acid. Significant changes were observed in the amino acids metabolism and the purine and pyrimidine metabolism. We also observed metabolic alterations in glycolysis, the citric acid cycle (TCA), and the pentose phosphate pathway. To expand the range of the detected polar metabolites and improve data confidence, we applied a global metabolomics profiling platform by using both non-targeted and targeted hydrophilic (HILIC)-LC-MS and GC-MS analysis. We used Ingenuity Knowledge Base to facilitate the projection of metabolomics data onto metabolic pathways. Several metabolic pathways showed differential responses to FK866 based on several matches to the list of annotated metabolites. This study suggests that global metabolomics can be a useful tool in pharmacological studies of the mechanism of action of drugs at a cellular level. PMID:25486521

  10. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer.

    Science.gov (United States)

    Matassa, D S; Amoroso, M R; Lu, H; Avolio, R; Arzeni, D; Procaccini, C; Faicchia, D; Maddalena, F; Simeon, V; Agliarulo, I; Zanini, E; Mazzoccoli, C; Recchi, C; Stronach, E; Marone, G; Gabra, H; Matarese, G; Landriscina, M; Esposito, F

    2016-09-01

    Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC.

  11. Metabolomics analysis of metabolic effects of nicotinamide phosphoribosyltransferase (NAMPT) inhibition on human cancer cells.

    Science.gov (United States)

    Tolstikov, Vladimir; Nikolayev, Alexander; Dong, Sucai; Zhao, Genshi; Kuo, Ming-Shang

    2014-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) plays an important role in cellular bioenergetics. It is responsible for converting nicotinamide to nicotinamide adenine dinucleotide, an essential molecule in cellular metabolism. NAMPT has been extensively studied over the past decade due to its role as a key regulator of nicotinamide adenine dinucleotide-consuming enzymes. NAMPT is also known as a potential target for therapeutic intervention due to its involvement in disease. In the current study, we used a global mass spectrometry-based metabolomic approach to investigate the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on metabolic perturbations in human cancer cells. We treated A2780 (ovarian cancer) and HCT-116 (colorectal cancer) cell lines with FK866 in the presence and absence of nicotinic acid. Significant changes were observed in the amino acids metabolism and the purine and pyrimidine metabolism. We also observed metabolic alterations in glycolysis, the citric acid cycle (TCA), and the pentose phosphate pathway. To expand the range of the detected polar metabolites and improve data confidence, we applied a global metabolomics profiling platform by using both non-targeted and targeted hydrophilic (HILIC)-LC-MS and GC-MS analysis. We used Ingenuity Knowledge Base to facilitate the projection of metabolomics data onto metabolic pathways. Several metabolic pathways showed differential responses to FK866 based on several matches to the list of annotated metabolites. This study suggests that global metabolomics can be a useful tool in pharmacological studies of the mechanism of action of drugs at a cellular level.

  12. Metabolomics analysis of metabolic effects of nicotinamide phosphoribosyltransferase (NAMPT inhibition on human cancer cells.

    Directory of Open Access Journals (Sweden)

    Vladimir Tolstikov

    Full Text Available Nicotinamide phosphoribosyltransferase (NAMPT plays an important role in cellular bioenergetics. It is responsible for converting nicotinamide to nicotinamide adenine dinucleotide, an essential molecule in cellular metabolism. NAMPT has been extensively studied over the past decade due to its role as a key regulator of nicotinamide adenine dinucleotide-consuming enzymes. NAMPT is also known as a potential target for therapeutic intervention due to its involvement in disease. In the current study, we used a global mass spectrometry-based metabolomic approach to investigate the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on metabolic perturbations in human cancer cells. We treated A2780 (ovarian cancer and HCT-116 (colorectal cancer cell lines with FK866 in the presence and absence of nicotinic acid. Significant changes were observed in the amino acids metabolism and the purine and pyrimidine metabolism. We also observed metabolic alterations in glycolysis, the citric acid cycle (TCA, and the pentose phosphate pathway. To expand the range of the detected polar metabolites and improve data confidence, we applied a global metabolomics profiling platform by using both non-targeted and targeted hydrophilic (HILIC-LC-MS and GC-MS analysis. We used Ingenuity Knowledge Base to facilitate the projection of metabolomics data onto metabolic pathways. Several metabolic pathways showed differential responses to FK866 based on several matches to the list of annotated metabolites. This study suggests that global metabolomics can be a useful tool in pharmacological studies of the mechanism of action of drugs at a cellular level.

  13. Urinary Metabolic Phenotyping Reveals Differences in the Metabolic Status of Healthy and Inflammatory Bowel Disease (IBD Children in Relation to Growth and Disease Activity

    Directory of Open Access Journals (Sweden)

    Francois-Pierre Martin

    2016-08-01

    Full Text Available Background: Growth failure and delayed puberty are well known features of children and adolescents with inflammatory bowel disease (IBD, in addition to the chronic course of the disease. Urinary metabonomics was applied in order to better understand metabolic changes between healthy and IBD children. Methods: 21 Pediatric patients with IBD (mean age 14.8 years, 8 males were enrolled from the Pediatric Gastroenterology Outpatient Clinic over two years. Clinical and biological data were collected at baseline, 6, and 12 months. 27 healthy children (mean age 12.9 years, 16 males were assessed at baseline. Urine samples were collected at each visit and subjected to 1H Nuclear Magnetic Resonance (NMR spectroscopy. Results: Using 1H NMR metabonomics, we determined that urine metabolic profiles of IBD children differ significantly from healthy controls. Metabolic differences include central energy metabolism, amino acid, and gut microbial metabolic pathways. The analysis described that combined urinary urea and phenylacetylglutamine—two readouts of nitrogen metabolism—may be relevant to monitor metabolic status in the course of disease. Conclusion: Non-invasive sampling of urine followed by metabonomic profiling can elucidate and monitor the metabolic status of children in relation to disease status. Further developments of omic-approaches in pediatric research might deliver novel nutritional and metabolic hypotheses.

  14. Urinary Metabolic Phenotyping Reveals Differences in the Metabolic Status of Healthy and Inflammatory Bowel Disease (IBD) Children in Relation to Growth and Disease Activity

    Science.gov (United States)

    Martin, Francois-Pierre; Ezri, Jessica; Cominetti, Ornella; Da Silva, Laeticia; Kussmann, Martin; Godin, Jean-Philippe; Nydegger, Andreas

    2016-01-01

    Background: Growth failure and delayed puberty are well known features of children and adolescents with inflammatory bowel disease (IBD), in addition to the chronic course of the disease. Urinary metabonomics was applied in order to better understand metabolic changes between healthy and IBD children. Methods: 21 Pediatric patients with IBD (mean age 14.8 years, 8 males) were enrolled from the Pediatric Gastroenterology Outpatient Clinic over two years. Clinical and biological data were collected at baseline, 6, and 12 months. 27 healthy children (mean age 12.9 years, 16 males) were assessed at baseline. Urine samples were collected at each visit and subjected to 1H Nuclear Magnetic Resonance (NMR) spectroscopy. Results: Using 1H NMR metabonomics, we determined that urine metabolic profiles of IBD children differ significantly from healthy controls. Metabolic differences include central energy metabolism, amino acid, and gut microbial metabolic pathways. The analysis described that combined urinary urea and phenylacetylglutamine—two readouts of nitrogen metabolism—may be relevant to monitor metabolic status in the course of disease. Conclusion: Non-invasive sampling of urine followed by metabonomic profiling can elucidate and monitor the metabolic status of children in relation to disease status. Further developments of omic-approaches in pediatric research might deliver novel nutritional and metabolic hypotheses. PMID:27529220

  15. Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk

    Institute of Scientific and Technical Information of China (English)

    Lucia Pacifico; Valerio Nobili; Caterina Anania; Paola Verdecchia; Claudio Chiesa

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, nonalcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.

  16. Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk.

    Science.gov (United States)

    Pacifico, Lucia; Nobili, Valerio; Anania, Caterina; Verdecchia, Paola; Chiesa, Claudio

    2011-07-14

    Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.

  17. Cis-regulatory mutations in human disease.

    Science.gov (United States)

    Epstein, Douglas J

    2009-07-01

    Cis-acting regulatory sequences are required for the proper temporal and spatial control of gene expression. Variation in gene expression is highly heritable and a significant determinant of human disease susceptibility. The diversity of human genetic diseases attributed, in whole or in part, to mutations in non-coding regulatory sequences is on the rise. Improvements in genome-wide methods of associating genetic variation with human disease and predicting DNA with cis-regulatory potential are two of the major reasons for these recent advances. This review will highlight select examples from the literature that have successfully integrated genetic and genomic approaches to uncover the molecular basis by which cis-regulatory mutations alter gene expression and contribute to human disease. The fine mapping of disease-causing variants has led to the discovery of novel cis-acting regulatory elements that, in some instances, are located as far away as 1.5 Mb from the target gene. In other cases, the prior knowledge of the regulatory landscape surrounding the gene of interest aided in the selection of enhancers for mutation screening. The success of these studies should provide a framework for following up on the large number of genome-wide association studies that have identified common variants in non-coding regions of the genome that associate with increased risk of human diseases including, diabetes, autism, Crohn's, colorectal cancer, and asthma, to name a few.

  18. Crosstalk of metabolic factors and neurogenic signaling in adult neurogenesis: Implication of metabolic regulation for mental and neurological diseases.

    Science.gov (United States)

    Gao, Chong; Wang, Qi; Chung, Sookja K; Shen, Jiangang

    2017-02-07

    Metabolic disorders like diabetes and obesity are commonly companied with neurological diseases and psychiatric disorders. Accumulating evidences indicated that cellular metabolic factors affect adult neurogenesis and have modulating effects on neurodegenerative disorders and psychiatric diseases. Adult neurogenesis contains multiple steps including proliferation of neural stem cells, lineage commitments of neural progenitor cells, maturation into functional neurons, and integration into neuronal network. Many intrinsic and extrinsic factors produced from neural stem/progenitor cells and their microenvironment or neurogenic niche take roles in modulating neurogenesis and contribute to the brain repair and functional recoveries in many neurological diseases and psychiatric disorders. In this article, we review current progress about how different growth factors, neurotrophin, neurotransmitters and transcriptional factors work on regulating neurogenic process. In particular, we emphasize the roles of the cellular metabolic factors, such as insulin/IGF signaling, incretins, and lipid metabolic signaling molecules in modulating adult neurogenesis, and discuss their impacts on neurological behaviors. We propose that the metabolic factors could be the new therapeutic targets for adult neurogenesis. Plus, the metabolism-regulating drugs have the potentials for treatment of neurodegenerative diseases and mental disorders.

  19. Human gene therapy and imaging in neurological diseases

    Energy Technology Data Exchange (ETDEWEB)

    Jacobs, Andreas H.; Winkler, Alexandra [Max Planck-Institute for Neurological Research, Center of Molecular Medicine (CMMC) and Department of Neurology, Cologne (Germany); MPI for Neurological Research, Laboratory for Gene Therapy and Molecular Imaging, Cologne (Germany); Castro, Maria G.; Lowenstein, Pedro [University of California Los Angeles (United States). Department of Medicine

    2005-12-01

    Molecular imaging aims to assess non-invasively disease-specific biological and molecular processes in animal models and humans in vivo. Apart from precise anatomical localisation and quantification, the most intriguing advantage of such imaging is the opportunity it provides to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Further, molecular imaging can be used to address basic scientific questions, e.g. transcriptional regulation, signal transduction or protein/protein interaction, and will be essential in developing treatment strategies based on gene therapy. Most importantly, molecular imaging is a key technology in translational research, helping to develop experimental protocols which may later be applied to human patients. Over the past 20 years, imaging based on positron emission tomography (PET) and magnetic resonance imaging (MRI) has been employed for the assessment and ''phenotyping'' of various neurological diseases, including cerebral ischaemia, neurodegeneration and brain gliomas. While in the past neuro-anatomical studies had to be performed post mortem, molecular imaging has ushered in the era of in vivo functional neuro-anatomy by allowing neuroscience to image structure, function, metabolism and molecular processes of the central nervous system in vivo in both health and disease. Recently, PET and MRI have been successfully utilised together in the non-invasive assessment of gene transfer and gene therapy in humans. To assess the efficiency of gene transfer, the same markers are being used in animals and humans, and have been applied for phenotyping human disease. Here, we review the imaging hallmarks of focal and disseminated neurological diseases, such as cerebral ischaemia, neurodegeneration and glioblastoma multiforme, as well as the attempts to translate gene therapy's experimental knowledge into clinical applications and the way in which this process is being

  20. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease.

    Science.gov (United States)

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-09-14

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as "fatty infiltration" or "nonalcoholic fatty pancreas disease" (NAFPD). The term "fatty replacement" describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of "ectopic fat deposition", which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula.

  1. Copper metabolic defects and liver disease: environmental aspects.

    Science.gov (United States)

    Pankit, Anand N; Bhave, Sheila A

    2002-12-01

    Copper (Cu) is an essential trace element for many biological processes. Cu homeostasis is generally well maintained by inbuilt controls in intestinal absorption, biliary excretion and intrahepatic storage. Copper deficiency disorders are rare. Acute Cu toxicity occurs occasionally in accidental poisoning with Cu sulfate. Chronic Cu toxicity in the form of liver cirrhosis and damage to other organs is seen classically in Wilson's Disease (genetic abnormality of Cu metabolism) and in the presumed environmental disorder Indian Childhood Cirrhosis (ICC). The clinical, epidemiological and treatment aspects of ICC are described. The evidence linking ICC to environmental Cu is (i) greatly increased hepatic Cu; (ii) early introduction of Cu contaminated milk boiled or stored in brass vessels; (iii) dramatic decline in ICC throughout the country coincident with change in feeding vessels; and (iv) continued long-term remission in d-penicillamine-treated patients after withdrawal of the drug. The nature and role of a second factor in the causation of ICC remains unclear, although a genetic predisposition is strongly suspected. Scattered reports of an ICC-like illness from the West (Idiopathic Cu Toxicosis, Endemic Tyrolean Infantile Cirrhosis), suggest that different mechanisms (environmental, genetic or both) can lead to the same end stage liver disease-'ecogenetic' disorders.

  2. Mapping gene associations in human mitochondria using clinical disease phenotypes.

    Directory of Open Access Journals (Sweden)

    Curt Scharfe

    2009-04-01

    Full Text Available Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects

  3. Strengthening research on relationship between metabolic syndrome and chronic liver disease

    Directory of Open Access Journals (Sweden)

    FAN Jiangao

    2013-12-01

    Full Text Available Metabolic syndrome is becoming a global epidemic disease, and it has been an important cause or risk factor for chronic liver disease in China. Recently, many studies have shown that metabolic syndrome is not only the important cause or risk factor for non-alcoholic fatty liver disease, but also closely associated with increased incidence of cirrhosis and liver cancer in patients with alcoholic liver disease, chronic hepatitis B and C, and cryptogenic liver disease. Moreover, chronic liver disease patients with metabolic syndrome have a significantly increased risk of type 2 diabetes and arteriosclerotic cardiovascular disease. These results suggest that hepatologists should pay more attention to the clinical research on the relationship between metabolic syndrome and liver disease and its management.

  4. Predicting Essential Metabolic Genome Content of Niche-Specific Enterobacterial Human Pathogens during Simulation of Host Environments.

    Directory of Open Access Journals (Sweden)

    Tong Ding

    Full Text Available Microorganisms have evolved to occupy certain environmental niches, and the metabolic genes essential for growth in these locations are retained in the genomes. Many microorganisms inhabit niches located in the human body, sometimes causing disease, and may retain genes essential for growth in locations such as the bloodstream and urinary tract, or growth during intracellular invasion of the hosts' macrophage cells. Strains of Escherichia coli (E. coli and Salmonella spp. are thought to have evolved over 100 million years from a common ancestor, and now cause disease in specific niches within humans. Here we have used a genome scale metabolic model representing the pangenome of E. coli which contains all metabolic reactions encoded by genes from 16 E. coli genomes, and have simulated environmental conditions found in the human bloodstream, urinary tract, and macrophage to determine essential metabolic genes needed for growth in each location. We compared the predicted essential genes for three E. coli strains and one Salmonella strain that cause disease in each host environment, and determined that essential gene retention could be accurately predicted using this approach. This project demonstrated that simulating human body environments such as the bloodstream can successfully lead to accurate computational predictions of essential/important genes.

  5. Predicting Essential Metabolic Genome Content of Niche-Specific Enterobacterial Human Pathogens during Simulation of Host Environments.

    Science.gov (United States)

    Ding, Tong; Case, Kyle A; Omolo, Morrine A; Reiland, Holly A; Metz, Zachary P; Diao, Xinyu; Baumler, David J

    2016-01-01

    Microorganisms have evolved to occupy certain environmental niches, and the metabolic genes essential for growth in these locations are retained in the genomes. Many microorganisms inhabit niches located in the human body, sometimes causing disease, and may retain genes essential for growth in locations such as the bloodstream and urinary tract, or growth during intracellular invasion of the hosts' macrophage cells. Strains of Escherichia coli (E. coli) and Salmonella spp. are thought to have evolved over 100 million years from a common ancestor, and now cause disease in specific niches within humans. Here we have used a genome scale metabolic model representing the pangenome of E. coli which contains all metabolic reactions encoded by genes from 16 E. coli genomes, and have simulated environmental conditions found in the human bloodstream, urinary tract, and macrophage to determine essential metabolic genes needed for growth in each location. We compared the predicted essential genes for three E. coli strains and one Salmonella strain that cause disease in each host environment, and determined that essential gene retention could be accurately predicted using this approach. This project demonstrated that simulating human body environments such as the bloodstream can successfully lead to accurate computational predictions of essential/important genes.

  6. Metabolic syndrome and peripheral artery disease: Two related conditions.

    Science.gov (United States)

    Oriol Torón, Pilar Ángeles; Badía Farré, Teresa; Romaguera Lliso, Amparo; Roda Diestro, Jovita

    2016-01-01

    To ascertain the prevalence of metabolic syndrome (MS) in patients with peripheral artery disease (PAD) at the Martorell primary care (PC) center. To analyze the differences in comorbidities and cardiovascular risk factors between patients with PAD with and without MS. A cross-sectional, descriptive study on patients diagnosed with PAD according to computerized clinical records of the Martorell PC center. Variables collected included age, sex, high blood pressure (HBP), dyslipidemia (DLP), diabetes (DM), smoking, obesity, cardiovascular disease (CVD), erectile dysfunction (ED), renal failure (RF), and oligoalbuminuria. An analysis comparing patients with and without MS was performed. There were 131 patients diagnosed with PAD, 104 (79%) of whom were male. Sixty-three (48.1%) also had MS. Patients with both PAD and MS had, as compared to those with PAD only, a higher prevalence of HBP (87.3 vs. 60.3%, P: 0.001), DLP (77.8 vs. 60.3%, P: 0.03), DM (69.8 vs. 30.9%, P<.001), obesity (25.4 vs. 10.3%, P: 0.03), CVD (42.9 vs. 19.1%); P: 0.004), ED (81.3 vs. 54.3%, P: 0.02), and RF (40.3 vs. 17.9%, P: 0.006). Patients with both PAD and MS had a higher prevalence of HBP, DLP, DM, and obesity. They also had more cardiovascular events and were significantly associated with pathological conditions highly relevant for cardiovascular prognosis such as erectile dysfunction and chronic kidney disease. Copyright © 2016 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

  7. Metabolic syndrome in patients with peripheral arterial disease.

    Science.gov (United States)

    Estirado, E; Lahoz, C; Laguna, F; García-Iglesias, F; González-Alegre, M T; Mostaza, J M

    2014-11-01

    The prevalence of metabolic syndrome (MS) in patients with peripheral arterial disease (PAD) and coronary or cerebrovascular disease is increasing, but it is not known whether this association also exists in patients with isolated PAD. The aim of the current study was to assess the prevalence of MS in patients with PAD who had no coronary or cerebrovascular disease, the prescription rate of evidence-based cardiovascular therapies and the attainment of therapeutic goals in patients with PAD and with and without MS. Multicenter, cross-sectional study of 3.934 patients aged ≥ 45 years with isolated PAD who were treated in primary care and specialized outpatient clinics during 2009. A diagnosis of PAD was reached for ankle brachial indices <0.9, a previous history of amputation or revascularization. In the overall population, the mean age was 67.6 years, 73.8% were males and 63% had MS (95% CI 61.5-64.3%). Patients with MS had a higher prevalence of cardiovascular risk factors and comorbidities, more severe PAD and higher prescription rate of evidence-based cardiovascular therapies. After adjusting for risk factors and comorbidity, there was a more frequent use of renin-angiotensin system blockers, beta-blockers, diuretics and statins among the patients with MS. A lower percentage of patients with MS achieved the therapeutic goals for blood pressure (22% vs. 41.5%, p<0.001). Similarly, a lower percentage of patients with diabetes achieved the glycated hemoglobin goals (44% vs. 53.1%, p<0.001), with no differences in LDL-cholesterol levels (29.8% vs. 39.1%, p=0.265). Patients with PAD have a high prevalence of MS. Patients with MS do not attain therapeutic goals as frequently as those without, despite taking more cardiovascular drugs. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  8. Lessons from "lower" organisms: what worms, flies, and zebrafish can teach us about human energy metabolism.

    Directory of Open Access Journals (Sweden)

    Amnon Schlegel

    2007-11-01

    Full Text Available A pandemic of metabolic diseases (atherosclerosis, diabetes mellitus, and obesity, unleashed by multiple social and economic factors beyond the control of most individuals, threatens to diminish human life span for the first time in the modern era. Given the redundancy and inherent complexity of processes regulating the uptake, transport, catabolism, and synthesis of nutrients, magic bullets to target these diseases will be hard to find. Recent studies using the worm Caenorhabditis elegans, the fly Drosophila melanogaster, and the zebrafish Danio rerio indicate that these "lower" metazoans possess unique attributes that should help in identifying, investigating, and even validating new pharmaceutical targets for these diseases. We summarize findings in these organisms that shed light on highly conserved pathways of energy homeostasis.

  9. mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases

    OpenAIRE

    Yang, Zhihong; Ming, Xiu-Fen

    2012-01-01

    The continuing increase in the prevalence of obesity and metabolic disorders such as type-II diabetes and an accelerating aging population globally will remain the major contributors to cardiovascular mortality and morbidity in the 21st century. It is well known that aging is highly associated with metabolic and cardiovascular diseases. Growing evidence also shows that obesity and metabolic diseases accelerate aging process. Studies in experimental animal models demonstrate similarity of meta...

  10. mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases

    OpenAIRE

    Yang, Zhihong; Ming, Xiu-Fen

    2012-01-01

    The continuing increase in the prevalence of obesity and metabolic disorders such as type-II diabetes and an accelerating aging population globally will remain the major contributors to cardiovascular mortality and morbidity in the 21st century. It is well known that aging is highly associated with metabolic and cardiovascular diseases. Growing evidence also shows that obesity and metabolic diseases accelerate aging process. Studies in experimental animal models demonstrate similarity of meta...

  11. Infection and Alzheimer's disease: the APOE epsilon4 connection and lipid metabolism.

    Science.gov (United States)

    Urosevic, Nadezda; Martins, Ralph N

    2008-05-01

    Microorganisms, bacteria and viruses may infect and cause a range of acute and chronic diseases in humans dependent on the genetic background, age, sex, immune and health status of the host, as well as on the nature, virulence and dose of infectious agent. Late onset Alzheimer's disease (AD) is a progressive neurodegenerative illness of broad aetiology with a strong genetic component and a significant contribution of age, sex and life style factors. Both infectious diseases and AD are characterised by an increased production of an array of immune mediators, cytokines, chemokines and complement proteins by the host cells as well as by changes in the host lipid metabolism. In this review, we re-examine a dangerous liaison between several viral and bacterial infections and the most significant genetic factor for AD, APOE epsilon4, and the possible impact of this alliance on AD development. This connection was discussed in the broader context of lipid metabolism and in the light of different capacity of various infectious agents, their toxic lipophilic products and host lipoprotein particles for binding to cell receptor(s).

  12. The microvasculature: a target for nutritional programming and later risk of cardio-metabolic disease.

    Science.gov (United States)

    Musa, M G; Torrens, C; Clough, G F

    2014-01-01

    There is compelling evidence that microvascular deficits affecting multiple tissues and organs play an important role in the aetiopathogenesis of cardio-metabolic disease. Furthermore, both in humans and animal models, deficits in small vessel structure and function can be detected early, often before the onset of macrovascular disease and the development of end-organ damage that is common to hypertension and obesity-associated clinical disorders. This article considers the growing evidence for the negative impact of an adverse maternal diet on the long-term health of her child, and how this can result in a disadvantageous vascular phenotype that extends to the microvascular bed. We describe how structural and functional modifications in the offspring microcirculation during development may represent an important and additional risk determinant to increase susceptibility to the development of cardio-metabolic disease in adult life and consider the cell-signalling pathways associated with endothelial dysfunction that may be 'primed' by the maternal environment. Published studies were identified that reported outcomes related to the microcirculation, endothelium, maternal diet and vascular programming using NCBI PubMed.gov, MEDLINE and ISI Web of Science databases from 1980 until April 2013 using pre-specified search terms. Information extracted from over 230 original reports and review articles was critically evaluated by the authors for inclusion in this review.

  13. Role of paraoxonase 1 (PON1) in organophosphate metabolism: Implications in neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Androutsopoulos, Vasilis P. [Center of Toxicology Science and Research, University of Crete, Heraklion, Crete (Greece); Kanavouras, Konstantinos [Laboratory of Neurological Sciences, University of Crete, Heraklion, Crete (Greece); Tsatsakis, Aristidis M., E-mail: aris@med.uoc.gr [Center of Toxicology Science and Research, University of Crete, Heraklion, Crete (Greece)

    2011-11-15

    Organophosphate pesticides are a class of compounds that are widely used in agricultural and rural areas. Paraoxonase 1 (PON1) is a phase-I enzyme that is involved in the hydrolysis of organophosphate esters. Environmental poisoning by organophosphate compounds has been the main driving force of previous research on PON1 enzymes. Recent discoveries in animal models have revealed the important role of the enzyme in lipid metabolism. However although PON1 function is well established in experimental models, the contribution of PON1 in neurodegenerative diseases remains unclear. In this minireview we summarize the involvement of PON1 genotypes in the occurrence of Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. A brief overview of latest epidemiological studies, regarding the two most important PON1 coding region polymorphisms PON1-L55M and PON1-Q192R is presented. Positive and negative associations of PON1 with disease occurrence are reported. Notably the MM and RR alleles contribute a risk enhancing effect for the development of some neurodegenerative diseases, which may be explained by the reduced lipoprotein free radical scavenging activity that may give rise to neuronal damage, through distinct mechanism. Conflicting findings that fail to support this postulate may represent the human population ethnic heterogeneity, different sample size and environmental parameters affecting PON1 status. We conclude that further epidemiological studies are required in order to address the exact contribution of PON1 genome in combination with organophosphate exposure in populations with neurodegenerative diseases.

  14. Bioactive Plant Metabolites in the Management of Non-Communicable Metabolic Diseases: Looking at Opportunities beyond the Horizon

    Directory of Open Access Journals (Sweden)

    Chandan Prasad

    2015-12-01

    Full Text Available There has been an unprecedented worldwide rise in non-communicable metabolic diseases (NCDs, particularly cardiovascular diseases (CVD and diabetes. While modern pharmacotherapy has decreased the mortality in the existing population, it has failed to stem the rise. Furthermore, a large segment of the world population cannot afford expensive pharmacotherapy. Therefore, there is an urgent need for inexpensive preventive measures to control the rise in CVD and diabetes and associated co-morbidities. The purpose of this review is to explore the role of food bioactives in prevention of NCDs. To this end, we have critically analyzed the possible utility of three classes of food bioactives: (a resistant starch, a metabolically resistant carbohydrate known to favorably modulate insulin secretion and glucose metabolism; (b cyclo (His-Pro, a food-derived cyclic dipeptides; and (c polyphenol-rich berries. Finally, we have also briefly outlined the strategies needed to prepare these food-bioactives for human use.

  15. Diet-induced metabolic hamster model of nonalcoholic fatty liver disease

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    Bhathena J

    2011-06-01

    Full Text Available Jasmine Bhathena, Arun Kulamarva, Christopher Martoni, Aleksandra Malgorzata Urbanska, Meenakshi Malhotra, Arghya Paul, Satya PrakashBiomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Artificial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, Québec, CanadaBackground: Obesity, hypercholesterolemia, elevated triglycerides, and type 2 diabetes are major risk factors for metabolic syndrome. Hamsters, unlike rats or mice, respond well to diet-induced obesity, increase body mass and adiposity on group housing, and increase food intake due to social confrontation-induced stress. They have a cardiovascular and hepatic system similar to that of humans, and can thus be a useful model for human pathophysiology.Methods: Experiments were planned to develop a diet-induced Bio F1B Golden Syrian hamster model of dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hamsters were fed a normal control diet, a high-fat/high-cholesterol diet, a high-fat/high-cholesterol/methionine-deficient/choline-devoid diet, and a high-fat/high-cholesterol/choline-deficient diet. Serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, atherogenic index, and body weight were quantified biweekly. Fat deposition in the liver was observed and assessed following lipid staining with hematoxylin and eosin and with oil red O.Results: In this study, we established a diet-induced Bio F1B Golden Syrian hamster model for studying dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hyperlipidemia and elevated serum glucose concentrations were induced using this diet. Atherogenic index was elevated, increasing the risk for a cardiovascular event. Histological analysis of liver specimens at the end of four weeks showed increased fat deposition in the liver of animals fed

  16. Serum metabolic profiling of human gastric cancer based on gas chromatography/mass spectrometry

    Directory of Open Access Journals (Sweden)

    Hu Song

    2012-01-01

    Full Text Available Research on molecular mechanisms of carcinogenesis plays an important role in diagnosing and treating gastric cancer. Metabolic profiling may offer the opportunity to understand the molecular mechanism of carcinogenesis and help to non-invasively identify the potential biomarkers for the early diagnosis of human gastric cancer. The aims of this study were to explore the underlying metabolic mechanisms of gastric cancer and to identify biomarkers associated with morbidity. Gas chromatography/mass spectrometry (GC/MS was used to analyze the serum metabolites of 30 Chinese gastric cancer patients and 30 healthy controls. Diagnostic models for gastric cancer were constructed using orthogonal partial least squares discriminant analysis (OPLS-DA. Acquired metabolomic data were analyzed by the nonparametric Wilcoxon test to find serum metabolic biomarkers for gastric cancer. The OPLS-DA model showed adequate discrimination between cancer and non-cancer cohorts while the model failed to discriminate different pathological stages (I-IV of gastric cancer patients. A total of 44 endogenous metabolites such as amino acids, organic acids, carbohydrates, fatty acids, and steroids were detected, of which 18 differential metabolites were identified with significant differences. A total of 13 variables were obtained for their greatest contribution in the discriminating OPLS-DA model [variable importance in the projection (VIP value >1.0], among which 11 metabolites were identified using both VIP values (VIP >1 and the Wilcoxon test. These metabolites potentially revealed perturbations of glycolysis and of amino acid, fatty acid, cholesterol, and nucleotide metabolism of gastric cancer patients. These results suggest that gastric cancer serum metabolic profiling has great potential in detecting this disease and helping to understand its metabolic mechanisms.

  17. Engineering large animal models of human disease.

    Science.gov (United States)

    Whitelaw, C Bruce A; Sheets, Timothy P; Lillico, Simon G; Telugu, Bhanu P

    2016-01-01

    The recent development of gene editing tools and methodology for use in livestock enables the production of new animal disease models. These tools facilitate site-specific mutation of the genome, allowing animals carrying known human disease mutations to be produced. In this review, we describe the various gene editing tools and how they can be used for a range of large animal models of diseases. This genomic technology is in its infancy but the expectation is that through the use of gene editing tools we will see a dramatic increase in animal model resources available for both the study of human disease and the translation of this knowledge into the clinic. Comparative pathology will be central to the productive use of these animal models and the successful translation of new therapeutic strategies.

  18. Lipidomics of human brain aging and Alzheimer's disease pathology.

    Science.gov (United States)

    Naudí, Alba; Cabré, Rosanna; Jové, Mariona; Ayala, Victoria; Gonzalo, Hugo; Portero-Otín, Manuel; Ferrer, Isidre; Pamplona, Reinald

    2015-01-01

    Lipids stimulated and favored the evolution of the brain. Adult human brain contains a large amount of lipids, and the largest diversity of lipid classes and lipid molecular species. Lipidomics is defined as "the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation." Therefore, the study of brain lipidomics can help to unravel the diversity and to disclose the specificity of these lipid traits and its alterations in neural (neurons and glial) cells, groups of neural cells, brain, and fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of human brain aging and Alzheimer disease. This review will discuss the lipid composition of the adult human brain. We first consider a brief approach to lipid definition, classification, and tools for analysis from the new point of view that has emerged with lipidomics, and then turn to the lipid profiles in human brain and how lipids affect brain function. Finally, we focus on the current status of lipidomics findings in human brain aging and Alzheimer's disease pathology. Neurolipidomics will increase knowledge about physiological and pathological functions of brain cells and will place the concept of selective neuronal vulnerability in a lipid context. © 2015 Elsevier Inc. All rights reserved.

  19. Fatty acid metabolism studies of human epidermal cell cultures.

    Science.gov (United States)

    Marcelo, C L; Dunham, W R

    1993-12-01

    Adult human epidermal keratinocytes grow rapidly in medium that is essential fatty acid (EFA)-deficient. In this medium they exhibit decreased amounts of the fatty acids, 18:2, 20:3, 20:4, and contain increased amounts of monounsaturated fatty acids. [14C]- and [3H]acetate and radiolabeled fatty acids, 16:0, 18:2, and 20:4 were used to study the fatty acid metabolism of these cells. Label from acetate appeared in 14- to 20-carbon fatty acids, both saturated and monounsaturated. No label was seen in the essential fatty acid 18:2, 18:3, and 20:4. Radiolabel from [9, 10-3H]palmitic acid (16:0) was detected in 16:0, 16:1, 18:0, and 18:1. [14C]linoleic acid (18:2) was converted to 18:3, 20:2, 20:3, and 20:4, demonstrating delta 6 and delta 5 desaturase activity in keratinocytes. Label from acetate, 16:0, or 18:2 was found mostly in the cellular phospholipids while only one third of the label from [14C]arachidonic was found in the phospholipids. [14C]acetate and [14C]18:2 time course data were used to construct a model of the metabolism of these reactants, using coupled, first-order differential equations. The data show that EFA-deficient keratinocytes metabolize fatty acids using pathways previously found in liver; they suggest the positioning of 18:2 desaturase and 18:3 elongase near the plasma membrane; they indicate that for the synthesis of nonessential fatty acids the formation of 18:0 from 16:0 is the rate-determining step; and they show that the conversion of 18:2 to 20:3 is rapid. These experiments demonstrate a method to study lipid enzyme kinetics in living cells.

  20. Direct calorimetry: a brief historical review of its use in the study of human metabolism and thermoregulation.

    Science.gov (United States)

    Kenny, Glen P; Notley, Sean R; Gagnon, Daniel

    2017-07-08

    Direct calorimetry is the gold standard means of measuring human metabolic rate and its use has been fundamental for understanding metabolism in health and disease. While metabolic rate is now more commonly estimated indirectly from measures of the oxygen consumed during respiration, direct calorimetry provides the user with the unique capacity to quantify the heat produced from aerobic and anaerobic metabolism by measuring heat exchange between the body and the environment. This review provides a brief historical overview of the fundamental concepts which underlie direct calorimetry, of pioneer scientists which developed these concepts into functional pieces of equipment and the subsequent use of direct calorimetry to advance our understanding of energy balance, nutrition, and the pathogenesis of metabolic diseases. Attention is directed to seminal studies that successfully employed direct calorimetry to verify that the law of energy conservation also applies to human beings and to establish the validity of indirect calorimetry. Finally, we discuss the more recent use of direct calorimetry for the measurement of whole-body heat exchange and body heat storage in the study of human thermoregulation.

  1. Hypoglycaemia related to inherited metabolic diseases in adults

    Directory of Open Access Journals (Sweden)

    Douillard Claire

    2012-05-01

    Full Text Available Abstract In non-diabetic adult patients, hypoglycaemia may be related to drugs, critical illness, cortisol or glucagon insufficiency, non-islet cell tumour, insulinoma, or it may be surreptitious. Nevertheless, some hypoglycaemic episodes remain unexplained, and inborn errors of metabolism (IEM should be considered, particularly in cases of multisystemic involvement. In children, IEM are considered a differential diagnosis in cases of hypoglycaemia. In adulthood, IEM-related hypoglycaemia can persist in a previously diagnosed childhood disease. Hypoglycaemia may sometimes be a presenting sign of the IEM. Short stature, hepatomegaly, hypogonadism, dysmorphia or muscular symptoms are signs suggestive of IEM-related hypoglycaemia. In both adults and children, hypoglycaemia can be clinically classified according to its timing. Postprandial hypoglycaemia can be an indicator of either endogenous hyperinsulinism linked to non-insulinoma pancreatogenic hypoglycaemia syndrome (NIPHS, unknown incidence in adults or very rarely, inherited fructose intolerance. Glucokinase-activating mutations (one family are the only genetic disorder responsible for NIPH in adults that has been clearly identified so far. Exercise-induced hyperinsulinism is linked to an activating mutation of the monocarboxylate transporter 1 (one family. Fasting hypoglycaemia may be caused by IEM that were already diagnosed in childhood and persist into adulthood: glycogen storage disease (GSD type I, III, 0, VI and IX; glucose transporter 2 deficiency; fatty acid oxidation; ketogenesis disorders; and gluconeogenesis disorders. Fasting hypoglycaemia in adulthood can also be a rare presenting sign of an IEM, especially in GSD type III, fatty acid oxidation [medium-chain acyl-CoA dehydrogenase (MCAD, ketogenesis disorders (3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA lyase deficiency, and gluconeogenesis disorders (fructose-1,6-biphosphatase deficiency].

  2. Autonomous exoskeleton reduces metabolic cost of human walking.

    Science.gov (United States)

    Mooney, Luke M; Rouse, Elliott J; Herr, Hugh M

    2014-11-03

    Passive exoskeletons that assist with human locomotion are often lightweight and compact, but are unable to provide net mechanical power to the exoskeletal wearer. In contrast, powered exoskeletons often provide biologically appropriate levels of mechanical power, but the size and mass of their actuator/power source designs often lead to heavy and unwieldy devices. In this study, we extend the design and evaluation of a lightweight and powerful autonomous exoskeleton evaluated for loaded walking in (J Neuroeng Rehab 11:80, 2014) to the case of unloaded walking conditions. The metabolic energy consumption of seven study participants (85 ± 12 kg body mass) was measured while walking on a level treadmill at 1.4 m/s. Testing conditions included not wearing the exoskeleton and wearing the exoskeleton, in both powered and unpowered modes. When averaged across the gait cycle, the autonomous exoskeleton applied a mean positive mechanical power of 26 ± 1 W (13 W per ankle) with 2.12 kg of added exoskeletal foot-shank mass (1.06 kg per leg). Use of the leg exoskeleton significantly reduced the metabolic cost of walking by 35 ± 13 W, which was an improvement of 10 ± 3% (p = 0.023) relative to the control condition of not wearing the exoskeleton. The results of this study highlight the advantages of developing lightweight and powerful exoskeletons that can comfortably assist the body during walking.

  3. Glucose metabolism in cultured trophoblasts from human placenta

    Energy Technology Data Exchange (ETDEWEB)

    Moe, A.J.; Farmer, D.R.; Nelson, D.M.; Smith, C.H. (Washington Univ., St. Louis, MO (United States))

    1990-02-26

    The development of appropriate placental trophoblast isolation and culture techniques enables the study of pathways of glucose utilization by this important cell layer in vitro. Trophoblasts from normal term placentas were isolated and cultured 24 hours and 72 hours in uncoated polystyrene culture tubes or tubes previously coated with a fibrin matrix. Trophoblasts cultured on fibrin are morphologically distinct from those cultured on plastic or other matrices and generally resemble in vivo syncytium. Cells were incubated up to 3 hours with {sup 14}C-labeled glucose and reactions were stopped by addition of perchloric acid. {sup 14}CO{sub 2} production by trophoblasts increased linearly with time however the largest accumulation of label was in organic acids. Trophoblasts cultured in absence of fibrin utilized more glucose and accumulated more {sup 14}C in metabolic products compared to cells cultured on fibrin. Glucose oxidation to CO{sub 2} by the phosphogluconate (PG) pathway was estimated from specific yields of {sup 14}CO{sub 2} from (1-{sup 14}C)-D-glucose and (6-{sup 14}C)-D-glucose. Approximately 6% of glucose oxidation was by the PG pathway when cells were cultured on fibrin compared to approximately 1% by cells cultured in the absence of fibrin. The presence of a fibrin growth matrix appears to modulate the metabolism of glucose by trophoblast from human placenta in vitro.

  4. Targeting NAD+ metabolism in the human malaria parasite Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Jessica K O'Hara

    Full Text Available Nicotinamide adenine dinucleotide (NAD+ is an essential metabolite utilized as a redox cofactor and enzyme substrate in numerous cellular processes. Elevated NAD+ levels have been observed in red blood cells infected with the malaria parasite Plasmodium falciparum, but little is known regarding how the parasite generates NAD+. Here, we employed a mass spectrometry-based metabolomic approach to confirm that P. falciparum lacks the ability to synthesize NAD+ de novo and is reliant on the uptake of exogenous niacin. We characterized several enzymes in the NAD+ pathway and demonstrate cytoplasmic localization for all except the parasite nicotinamidase, which concentrates in the nucleus. One of these enzymes, the P. falciparum nicotinate mononucleotide adenylyltransferase (PfNMNAT, is essential for NAD+ metabolism and is highly diverged from the human homolog, but genetically similar to bacterial NMNATs. Our results demonstrate the enzymatic activity of PfNMNAT in vitro and demonstrate its ability to genetically complement the closely related Escherichia coli NMNAT. Due to the similarity of PfNMNAT to the bacterial enzyme, we tested a panel of previously identified bacterial NMNAT inhibitors and synthesized and screened twenty new derivatives, which demonstrate a range of potency against live parasite culture. These results highlight the importance of the parasite NAD+ metabolic pathway and provide both novel therapeutic targets and promising lead antimalarial compounds.

  5. Silibinin regulates lipid metabolism and differentiation in functional human adipocytes

    Directory of Open Access Journals (Sweden)

    Ignazio eBarbagallo

    2016-01-01

    Full Text Available Silibinin, a natural plant flavonoid, is the main active constituent found in milk thistle (Silybum marianum. It is known to have hepatoprotective, anti-neoplastic effect and suppresses lipid accumulation in adipocytes. Objective of this study was to investigate the effect of silibinin on adipogenic differentiation and thermogenic capacity of human adipose tissue derived mesenchymal stem cells. Silibinin (10 μM treatment, either at the beginning or at the end of adipogenic differentiation, resulted in an increase of SIRT-1, PPARα, Pgc-1α and UCPs gene expression. Moreover, silibinin administration resulted in a decrease of PPARγ, FABP4, FAS and MEST/PEG1 gene expression during the differentiation, confirming that this compound is able to reduce fatty acid accumulation and adipocyte size. Our data showed that silibinin regulated adipocyte lipid metabolism, inducing thermogenesis and promoting a brown remodelling in adipocyte. Taken together, our findings suggest that silibinin increases UCPs expression by stimulation of SIRT1, PPARα and Pgc-1α, improved metabolic parameters, decreased lipid mass leading to the formation of functional adipocytes.

  6. Progress and Challenges in Developing Metabolic Footprints from Diet in Human Gut Microbial Cometabolism12

    Science.gov (United States)

    Duffy, Linda C; Raiten, Daniel J; Hubbard, Van S; Starke-Reed, Pamela

    2015-01-01

    Homo sapiens harbor trillions of microbes, whose microbial metagenome (collective genome of a microbial community) using omic validation interrogation tools is estimated to be at least 100-fold that of human cells, which comprise 23,000 genes. This article highlights some of the current progress and open questions in nutrition-related areas of microbiome research. It also underscores the metabolic capabilities of microbial fermentation on nutritional substrates that require further mechanistic understanding and systems biology approaches of studying functional interactions between diet composition, gut microbiota, and host metabolism. Questions surrounding bacterial fermentation and degradation of dietary constituents (particularly by Firmicutes and Bacteroidetes) and deciphering how microbial encoding of enzymes and derived metabolites affect recovery of dietary energy by the host are more complex than previously thought. Moreover, it is essential to understand to what extent the intestinal microbiota is subject to dietary control and to integrate these data with functional metabolic signatures and biomarkers. Many lines of research have demonstrated the significant role of the gut microbiota in human physiology and disease. Probiotic and prebiotic products are proliferating in the market in response to consumer demand, and the science and technology around these products are progressing rapidly. With high-throughput molecular technologies driving the science, studying the bidirectional interactions of host-microbial cometabolism, epithelial cell maturation, shaping of innate immune development, normal vs. dysfunctional nutrient absorption and processing, and the complex signaling pathways involved is now possible. Substantiating the safety and mechanisms of action of probiotic/prebiotic formulations is critical. Beneficial modulation of the human microbiota by using these nutritional and biotherapeutic strategies holds considerable promise as next

  7. Nonoxidative ethanol metabolism in humans-from biomarkers to bioactive lipids.

    Science.gov (United States)

    Heier, Christoph; Xie, Hao; Zimmermann, Robert

    2016-12-01

    Ethanol is a widely used psychoactive drug whose chronic abuse is associated with organ dysfunction and disease. Although the prevalent metabolic fate of ethanol in the human body is oxidation a smaller fraction undergoes nonoxidative metabolism yielding ethyl glucuronide, ethyl sulfate, phosphatidylethanol and fatty acid ethyl esters. Nonoxidative ethanol metabolites persist in tissues and body fluids for much longer than ethanol itself and represent biomarkers for the assessment of ethanol intake in clinical and forensic settings. Of note, the nonoxidative reaction of ethanol with phospholipids and fatty acids yields bioactive compounds that affect cellular signaling pathways and organelle function and may contribute to ethanol toxicity. Thus, despite low quantitative contributions of nonoxidative pathways to overall ethanol metabolism the resultant ethanol metabolites have important biological implications. In this review we summarize the current knowledge about the enzymatic formation of nonoxidative ethanol metabolites in humans and discuss the implications of nonoxidative ethanol metabolites as biomarkers of ethanol intake and mediators of ethanol toxicity. © 2016 IUBMB Life, 68(12):916-923, 2016.

  8. [Metabolic acidosis in patients with chronic kidney diseases: why and when to treat it?].

    Science.gov (United States)

    Sofia, A; Cappelli, V; Valli, A; Garibotto, G

    2005-01-01

    Metabolic acidosis is a common complication in patients with advanced chronic renal diseases and dialytic treatments are unable to correct it completely. In hemodialysis (HD) patients, severe metabolic acidosis is associated with an increased risk of death. Evidence from several experimental studies suggests that even mild metabolic acidosis is associated with systemic effects. Acidosis is implicated in endocrine changes and has negative repercussions on bone and protein metabolism. In addition, recent observations suggest that acidosis triggers inflammation and accelerates the progression of chronic kidney diseases. As a contradictory finding, acidosis can reduce circulating leptin. Clinical studies on the nutritional effects of metabolic acidosis correction have shown mildly favorable effects. Taking into account the systemic effects of metabolic acidosis it is suggested that even mild metabolic acidosis is corrected. However, the new findings concerning the systemic effects of acidosis must be evaluated in controlled trials.

  9. Adipocyte cell death, fatty liver disease and associated metabolic disorders.

    Science.gov (United States)

    Eguchi, Akiko; Feldstein, Ariel E

    2014-01-01

    Obesity has reached epidemic proportions in the U.S.A. and many other parts of the world. Obesity increases the risk of a number of adverse health conditions including type 2 diabetes, insulin resistance, dyslipidemia, hypertension, and hepatic steatosis. Adipocyte hypertrophy occurs during weight gain and is associated with recruitment of immune cells, mainly macrophages, into the adipose tissue (AT). These cells typically surround a dying or dead adipocyte with the formation of crown-like structures that are present in experimental models of obesity as well as obese humans. The immune infiltration of AT results in increased production of various adipokines, cytokines, and chemokines that play a crucial role in the development of insulin resistance and hepatic steatosis. The pathogenic mechanisms resulting in AT macrophage recruitment are under intense investigation and remain incompletely understood. Recent evidence suggests that various programmed cell death pathways are activated in stressed hypertrophied adipocytes and may result in cell death. These events appear to occur at early stages and be important in triggering the metabolic dysregulation associated with obesity.

  10. Leptin in chronic kidney disease: a link between hematopoiesis, bone metabolism, and nutrition.

    Science.gov (United States)

    Zhang, Jingjing; Wang, Ningning

    2014-06-01

    Anemia, dyslipidemia, malnutrition, together with mineral and bone disorders are common complications in patients with chronic kidney disease (CKD). All are associated with increased risk of mortality. Leptin is a small peptide hormone that is mainly but not exclusively produced in adipose tissue. It is also secreted by normal human osteoblasts, subchondral osteoblasts, placental syncytiotrophoblasts, and the gastric epithelium. Leptin binds to its receptors in the hypothalamus to regulate bone metabolism and food intake. Leptin also has several other important metabolic effects on peripheral tissues, including the liver, skeletal muscle, and bone marrow. Leptin is cleared principally by the kidney. Not surprisingly, serum leptin appears to increase concurrently with declines in the glomerular filtration rate in patients with CKD. A growing body of evidence suggests that leptin might be closely related to hematopoiesis, nutrition, and bone metabolism in CKD patients. Results are conflicting regarding leptin in patients with CKD, in whom both beneficial and detrimental effects on uremia outcome are found. This review elucidates the discovery of leptin and its receptors, changes in serum or plasma leptin levels, the functions of leptin, relationships between leptin and the complications mentioned above, and pharmaceutical interventions in serum leptin levels in patients with CKD.

  11. Alzheimer's disease and natural cognitive aging may represent adaptive metabolism reduction programs

    Directory of Open Access Journals (Sweden)

    Reser Jared

    2009-02-01

    Full Text Available Abstract The present article examines several lines of converging evidence suggesting that the slow and insidious brain changes that accumulate over the lifespan, resulting in both natural cognitive aging and Alzheimer's disease (AD, represent a metabolism reduction program. A number of such adaptive programs are known to accompany aging and are thought to have decreased energy requirements for ancestral hunter-gatherers in their 30s, 40s and 50s. Foraging ability in modern hunter-gatherers declines rapidly, more than a decade before the average terminal age of 55 years. Given this, the human brain would have been a tremendous metabolic liability that must have been advantageously tempered by the early cellular and molecular changes of AD which begin to accumulate in all humans during early adulthood. Before the recent lengthening of life span, individuals in the ancestral environment died well before this metabolism reduction program resulted in clinical AD, thus there was never any selective pressure to keep adaptive changes from progressing to a maladaptive extent. Aging foragers may not have needed the same cognitive capacities as their younger counterparts because of the benefits of accumulated learning and life experience. It is known that during both childhood and adulthood metabolic rate in the brain decreases linearly with age. This trend is thought to reflect the fact that children have more to learn. AD "pathology" may be a natural continuation of this trend. It is characterized by decreasing cerebral metabolism, selective elimination of synapses and reliance on accumulating knowledge (especially implicit and procedural over raw brain power (working memory. Over decades of subsistence, the behaviors of aging foragers became routinized, their motor movements automated and their expertise ingrained to a point where they no longer necessitated the first-rate working memory they possessed when younger and learning actively. Alzheimer

  12. Distinct metabolic network states manifest in the gene expression profiles of pediatric inflammatory bowel disease patients and controls

    Science.gov (United States)

    Knecht, Carolin; Fretter, Christoph; Rosenstiel, Philip; Krawczak, Michael; Hütt, Marc-Thorsten

    2016-09-01

    Information on biological networks can greatly facilitate the function-orientated interpretation of high-throughput molecular data. Genome-wide metabolic network models of human cells, in particular, can be employed to contextualize gene expression profiles of patients with the goal of both, a better understanding of individual etiologies and an educated reclassification of (clinically defined) phenotypes. We analyzed publicly available expression profiles of intestinal tissues from treatment-naive pediatric inflammatory bowel disease (IBD) patients and age-matched control individuals, using a reaction-centric metabolic network derived from the Recon2 model. By way of defining a measure of ‘coherence’, we quantified how well individual patterns of expression changes matched the metabolic network. We observed a bimodal distribution of metabolic network coherence in both patients and controls, albeit at notably different mixture probabilities. Multidimensional scaling analysis revealed a bisectional pattern as well that overlapped widely with the metabolic network-based results. Expression differences driving the observed bimodality were related to cellular transport of thiamine and bile acid metabolism, thereby highlighting the crosstalk between metabolism and other vital pathways. We demonstrated how classical data mining and network analysis can jointly identify biologically meaningful patterns in gene expression data.

  13. Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

    OpenAIRE

    2015-01-01

    Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and c...

  14. Dysregulation of multiple facets of glycogen metabolism in a murine model of Pompe disease.

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    Kristin M Taylor

    Full Text Available Pompe disease, also known as glycogen storage disease (GSD type II, is caused by deficiency of lysosomal acid α-glucosidase (GAA. The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1 to 2 years of age to a slower progressive course that causes significant morbidity and early mortality in children and adults. The aim of this study is to better understand the biochemical consequences of glycogen accumulation in the Pompe mouse. We evaluated glycogen metabolism in heart, triceps, quadriceps, and liver from wild type and several strains of GAA(-/- mice. Unexpectedly, we observed that lysosomal glycogen storage correlated with a robust increase in factors that normally promote glycogen biosynthesis. The GAA(-/- mouse strains were found to have elevated glycogen synthase (GS, glycogenin, hexokinase, and glucose-6-phosphate (G-6-P, the allosteric activator of GS. Treating GAA(-/- mice with recombinant human GAA (rhGAA led to a dramatic reduction in the levels of glycogen, GS, glycogenin, and G-6-P. Lysosomal glycogen storage also correlated with a dysregulation of phosphorylase, which normally breaks down cytoplasmic glycogen. Analysis of phosphorylase activity confirmed a previous report that, although phosphorylase protein levels are identical in muscle lysates from wild type and GAA(-/- mice, phosphorylase activity is suppressed in the GAA(-/- mice in the absence of AMP. This reduction in phosphorylase activity likely exacerbates lysosomal glycogen accumulation. If the dysregulation in glycogen metabolism observed in the mouse model of Pompe disease also occurs in Pompe patients, it may contribute to the observed broad spectrum of disease severity.

  15. Dysregulation of Iron Metabolism in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

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    Satoru Oshiro

    2011-01-01

    Full Text Available Dysregulation of iron metabolism has been observed in patients with neurodegenerative diseases (NDs. Utilization of several importers and exporters for iron transport in brain cells helps maintain iron homeostasis. Dysregulation of iron homeostasis leads to the production of neurotoxic substances and reactive oxygen species, resulting in iron-induced oxidative stress. In Alzheimer's disease (AD and Parkinson's disease (PD, circumstantial evidence has shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation. Several genetic studies have revealed mutations in genes associated with increased iron uptake, increased oxidative stress, and an altered inflammatory response in amyotrophic lateral sclerosis (ALS. Here, we review the recent findings on brain iron metabolism in common NDs, such as AD, PD, and ALS. We also summarize the conventional and novel types of iron chelators, which can successfully decrease excess iron accumulation in brain lesions. For example, iron-chelating drugs have neuroprotective effects, preventing neural apoptosis, and activate cellular protective pathways against oxidative stress. Glial cells also protect neurons by secreting antioxidants and antiapoptotic substances. These new findings of experimental and clinical studies may provide a scientific foundation for advances in drug development for NDs.

  16. Abnormalities in Glutamate Metabolism and Excitotoxicity in the Retinal Diseases

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    Makoto Ishikawa

    2013-01-01

    Full Text Available In the physiological condition, glutamate acts as an excitatory neurotransmitter in the retina. However, excessive glutamate can be toxic to retinal neurons by overstimulation of the glutamate receptors. Glutamate excess is primarily attributed to perturbation in the homeostasis of the glutamate metabolism. Major pathway of glutamate metabolism consists of glutamate uptake by glutamate transporters followed by enzymatic conversion of glutamate to nontoxic glutamine by glutamine synthetase. Glutamate metabolism requires energy supply, and the energy loss inhibits the functions of both glutamate transporters and glutamine synthetase. In this review, we describe the present knowledge concerning the retinal glutamate metabolism under the physiological and pathological conditions.

  17. Pathway-selective insulin resistance and metabolic disease: the importance of nutrient flux.

    Science.gov (United States)

    Otero, Yolanda F; Stafford, John M; McGuinness, Owen P

    2014-07-25

    Hepatic glucose and lipid metabolism are altered in metabolic disease (e.g. obesity, metabolic syndrome, and Type 2 diabetes). Insulin-dependent regulation of glucose metabolism is impaired. In contrast, lipogenesis, hypertriglyceridemia, and hepatic steatosis are increased. Because insulin promotes lipogenesis and liver fat accumulation, to explain the elevation in plasma and tissue lipids, investigators have suggested the presence of pathway-selective insulin resistance. In this model, insulin signaling to glucose metabolism is impaired, but insulin signaling to lipid metabolism is intact. We discuss the evidence for the differential regulation of hepatic lipid and glucose metabolism. We suggest that the primary phenotypic driver is altered substrate delivery to the liver, as well as the repartitioning of hepatic nutrient handling. Specific alterations in insulin signaling serve to amplify the alterations in hepatic substrate metabolism. Thus, hyperinsulinemia and its resultant increased signaling may facilitate lipogenesis, but are not the major drivers of the phenotype of pathway-selective insulin resistance.

  18. Therapeutics Targeting FGF Signaling Network in Human Diseases.

    Science.gov (United States)

    Katoh, Masaru

    2016-12-01

    Fibroblast growth factor (FGF) signaling through its receptors, FGFR1, FGFR2, FGFR3, or FGFR4, regulates cell fate, angiogenesis, immunity, and metabolism. Dysregulated FGF signaling causes human diseases, such as breast cancer, chondrodysplasia, gastric cancer, lung cancer, and X-linked hypophosphatemic rickets. Recombinant FGFs are pro-FGF signaling therapeutics for tissue and/or wound repair, whereas FGF analogs and gene therapy are under development for the treatment of cardiovascular disease, diabetes, and osteoarthritis. FGF traps, anti-FGF/FGFR monoclonal antibodies (mAbs), and small-molecule FGFR inhibitors are anti-FGF signaling therapeutics under development for the treatment of cancer, chondrodysplasia, and rickets. Here, I discuss the benefit-risk and cost-effectiveness issues of precision medicine targeting FGFRs, ALK, EGFR, and FLT3. FGFR-targeted therapy should be optimized for cancer treatment, focusing on genomic tests and recurrence.

  19. Adiponectin: an attractive marker for metabolic disorders in Chronic Obstructive Pulmonary Disease (COPD).

    Science.gov (United States)

    Bianco, Andrea; Mazzarella, Gennaro; Turchiarelli, Viviana; Nigro, Ersilia; Corbi, Graziamaria; Scudiero, Olga; Sofia, Matteo; Daniele, Aurora

    2013-10-14

    Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory lung disease which may be complicated by development of co-morbidities including metabolic disorders. Metabolic disorders commonly associated with this disease contribute to lung function impairment and mortality. Systemic inflammation appears to be a major factor linking COPD to metabolic alterations. Adipose tissue seems to interfere with systemic inflammation in COPD patients by producing a large number of proteins, known as "adipokines", involved in various processes such as metabolism, immunity and inflammation. There is evidence that adiponectin is an important modulator of inflammatory processes implicated in airway pathophysiology. Increased serum levels of adiponectin and expression of its receptors on lung tissues of COPD patients have recently highlighted the importance of the adiponectin pathway in this disease. Further, in vitro studies have demonstrated an anti-inflammatory activity for this adipokine at the level of lung epithelium. This review focuses on mechanisms by which adiponectin is implicated in linking COPD with metabolic disorders.

  20. Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling.

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    Sven van Eijl

    Full Text Available BACKGROUND: Human skin has the capacity to metabolise foreign chemicals (xenobiotics, but knowledge of the various enzymes involved is incomplete. A broad-based unbiased proteomics approach was used to describe the profile of xenobiotic metabolising enzymes present in human skin and hence indicate principal routes of metabolism of xenobiotic compounds. Several in vitro models of human skin have been developed for the purpose of safety assessment of chemicals. The suitability of these epidermal models for studies involving biotransformation was assessed by comparing their profiles of xenobiotic metabolising enzymes with those of human skin. METHODOLOGY/PRINCIPAL FINDINGS: Label-free proteomic analysis of whole human skin (10 donors was applied and analysed using custom-built PROTSIFT software. The results showed the presence of enzymes with a capacity for the metabolism of alcohols through dehydrogenation, aldehydes through dehydrogenation and oxidation, amines through oxidation, carbonyls through reduction, epoxides and carboxylesters through hydrolysis and, of many compounds, by conjugation to glutathione. Whereas protein levels of these enzymes in skin were mostly just 4-10 fold lower than those in liver and sufficient to support metabolism, the levels of cytochrome P450 enzymes were at least 300-fold lower indicating they play no significant role. Four epidermal models of human skin had profiles very similar to one another and these overlapped substantially with that of whole skin. CONCLUSIONS/SIGNIFICANCE: The proteomics profiling approach was successful in producing a comprehensive analysis of the biotransformation characteristics of whole human skin and various in vitro skin models. The results show that skin contains a range of defined enzymes capable of metabolising different classes of chemicals. The degree of similarity of the profiles of the in vitro models indicates their suitability for epidermal toxicity testing. Overall, these

  1. Modeling human muscle disease in zebrafish

    OpenAIRE

    Guyon, Jeffrey R.; Steffen, Leta S; Howell, Melanie H.; Pusack, Timothy J; Lawrence, Chris; Kunkel, Louis M

    2007-01-01

    Modeling human muscle disease in zebrafish correspondence: Corresponding author. Children's Hospital Boston, Enders Bldg, Rm 570, 300 Longwood Ave Boston, MA 02115. Tel.: +1 617 355 7576. (Kunkel, Louis M.) (Kunkel, Louis M.) Program in Genomics and Howard Hughes Medical Institute at Children's Hospital Boston - Boston--> , MA 02115--> - UNITED STATES (Guyon, Jeffrey R.) Program in Genomics a...

  2. MEMBRANE BILE ACID RECEPTOR TGR5 - A NEW TARGET IN THE STUDY OF METABOLIC, INFLAMMATORY AND NEOPLASTIC DISEASES

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    O. M. Drapkina

    2016-01-01

    Full Text Available TGR5 are G-protein-linked, membrane bile acids receptors that widely express in tissues of animals and humans. Namely tissue localization of TGR5 determines biological effects of activation of these receptors. This review focuses on the role of TGR5 as a new pharmacological target for the treatment of patients with metabolic syndrome, diabetes, obesity, atherosclerosis, liver disease and cancer processes.

  3. Dietary monounsaturated fatty acids are protective against metabolic syndrome and cardiovascular disease risk factors.

    Science.gov (United States)

    Gillingham, Leah G; Harris-Janz, Sydney; Jones, Peter J H

    2011-03-01

    Over 50 years of research has sought to define the role dietary fat plays in cardiovascular disease (CVD) risk. Although optimal dietary fat quantity has been keenly pursued over past decades, attention has recently centered on the value of dietary fat quality. The purpose of the present review is to provide a critical assessment of the current body of evidence surrounding efficacy of dietary monounsaturated fatty acids (MUFA) for reduction of traditional risk factors defining metabolic syndrome (MetS) and CVD. Due to existing and emerging research on health attributes of MUFA rich diets, and to the low prevalence of chronic disease in populations consuming MUFA rich Mediterranean diets, national dietary guidelines are increasingly recommending dietary MUFA, primarily at the expense of saturated fatty acids (SFA). Consumption of dietary MUFA promotes healthy blood lipid profiles, mediates blood pressure, improves insulin sensitivity and regulates glucose levels. Moreover, provocative newer data suggest a role for preferential oxidation and metabolism of dietary MUFA, influencing body composition and ameliorating the risk of obesity. Mounting epidemiological and human clinical trial data continue to demonstrate the cardioprotective activity of the MUFA content of dietary fat. As the debate on the optimal fatty acid composition of the diet continues, the benefit of increasing MUFA intakes, particularly as a substitute for dietary SFA, deserves considerable attention.

  4. Redox metabolism abnormalities in autistic children associated with mitochondrial disease.

    Science.gov (United States)

    Frye, R E; Delatorre, R; Taylor, H; Slattery, J; Melnyk, S; Chowdhury, N; James, S J

    2013-06-18

    Research studies have uncovered several metabolic abnormalities associated with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal redox metabolism. Despite the close connection between mitochondrial dysfunction and oxidative stress, the relation between MD and oxidative stress in children with ASD has not been studied. Plasma markers of oxidative stress and measures of cognitive and language development and ASD behavior were obtained from 18 children diagnosed with ASD who met criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD). Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language was measured using the preschool language scale or the expressive one-word vocabulary test (depending on the age), adaptive behaviour was measured using the Vineland Adaptive Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have lower scores on the communication and daily living skill subscales of the VABS despite having similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD, suggesting an overall more favourable glutathione redox status in the ASD/MD group. However, compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG, demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had higher levels of 3CT than younger ASD/NoMD children because of an age-related effect in the ASD/MD group. Both ASD groups demonstrated significantly

  5. Disorders of phospholipid metabolism: an emerging class of mitochondrial disease due to defects in nuclear genes

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    Ya-Wen eLu

    2015-02-01

    Full Text Available The human nuclear and mitochondrial genomes co-exist within each cell. While the mitochondrial genome encodes for a limited number of proteins, transfer RNAs, and ribosomal RNAs, the vast majority of mitochondrial proteins are encoded in the nuclear genome. Of the multitude of mitochondrial disorders known to date, only a fifth are maternally inherited. The recent characterization of the mitochondrial proteome therefore serves as an important step towards delineating the nosology of a large spectrum of phenotypically heterogeneous diseases. Following the identification of the first nuclear gene defect to underlie a mitochondrial disorder, a plenitude of genetic variants that provoke mitochondrial pathophysiology have been molecularly elucidated and classified into six categories that impact: 1 oxidative phosphorylation (subunits and assembly factors; 2 mitochondrial DNA maintenance and expression; 3 mitochondrial protein import and assembly; 4 mitochondrial quality control (chaperones and proteases; 5 iron-sulfur cluster homeostasis; and 6 mitochondrial dynamics (fission and fusion. Here, we propose that an additional class of genetic variant be included in the classification schema to acknowledge the role of genetic defects in phospholipid biosynthesis, remodeling, and metabolism in mitochondrial pathophysiology. This seventh class includes a small but notable group of nuclear-encoded proteins whose dysfunction impacts normal mitochondrial phospholipid metabolism. The resulting human disorders present with a diverse array of pathologic consequences that reflect the variety of functions that phospholipids have in mitochondria and highlight the important role of proper membrane homeostasis in mitochondrial biology.

  6. [Human prion diseases in the Czech Republic].

    Science.gov (United States)

    Rohan, Z; Rusina, R; Marešová, M; Matěj, R

    2015-09-01

    Human prion diseases are a group of very rare diseases with a unique pathogenesis and, due to an inauspicious prognosis and unavailability of therapy, with fatal consequences. The etiopathogenetic background is the presence of pathologically misfolded prion protein, highly resistant to denaturation, the aggregation and presence of which in the brain tissue causes irreversible neuronal damage. The most frequent prion disease in humans is Creutzfeldt-Jakob disease (CJD) which occurs in sporadic, hereditary/familial, or acquired/infectious/iatrogenic forms. A new form of CJD, variant CJD, is considered to be linked to dietary exposure to beef products from cattle infected with bovine spongiform encephalopathy (BSE) and to infection via blood transfusion. The clinical picture of these diseases is characterized by a rapidly progressing dementia, cerebellar and extrapyramidal symptoms, and rather specific MRI, EEG, and CSF findings. Clinically, the diagnosis is described as possible or probable prion disease and needs to be confirmed by neuropathological or immunological investigation of the brain tissue. Epidemiological data from the Czech Republic spanning the last decade are presented.

  7. Recent developments on the role of epigenetics in obesity and metabolic disease.

    Science.gov (United States)

    van Dijk, Susan J; Tellam, Ross L; Morrison, Janna L; Muhlhausler, Beverly S; Molloy, Peter L

    2015-01-01

    The increased prevalence of obesity and related comorbidities is a major public health problem. While genetic factors undoubtedly play a role in determining individual susceptibility to weight gain and obesity, the identified genetic variants only explain part of the variation. This has led to growing interest in understanding the potential role of epigenetics as a mediator of gene-environment interactions underlying the development of obesity and its associated comorbidities. Initial evidence in support of a role of epigenetics in obesity and type 2 diabetes mellitus (T2DM) was mainly provided by animal studies, which reported epigenetic changes in key metabolically important tissues following high-fat feeding and epigenetic differences between lean and obese animals and by human studies which showed epigenetic changes in obesity and T2DM candidate genes in obese/diabetic individuals. More recently, advances in epigenetic methodologies and the reduced cost of epigenome-wide association studies (EWAS) have led to a rapid expansion of studies in human populations. These studies have also reported epigenetic differences between obese/T2DM adults and healthy controls and epigenetic changes in association with nutritional, weight loss, and exercise interventions. There is also increasing evidence from both human and animal studies that the relationship between perinatal nutritional exposures and later risk of obesity and T2DM may be mediated by epigenetic changes in the offspring. The aim of this review is to summarize the most recent developments in this rapidly moving field, with a particular focus on human EWAS and studies investigating the impact of nutritional and lifestyle factors (both pre- and postnatal) on the epigenome and their relationship to metabolic health outcomes. The difficulties in distinguishing consequence from causality in these studies and the critical role of animal models for testing causal relationships and providing insight into underlying

  8. Metformin and metabolic diseases: a focus on hepatic aspects.

    Science.gov (United States)

    Zheng, Juan; Woo, Shih-Lung; Hu, Xiang; Botchlett, Rachel; Chen, Lulu; Huo, Yuqing; Wu, Chaodong

    2015-06-01

    Metformin has been widely used as a first-line anti-diabetic medicine for the treatment of type 2 diabetes (T2D). As a drug that primarily targets the liver, metformin suppresses hepatic glucose production (HGP), serving as the main mechanism by which metformin improves hyperglycemia of T2D. Biochemically, metformin suppresses gluconeogenesis and stimulates glycolysis. Metformin also inhibits glycogenolysis, which is a pathway that critically contributes to elevated HGP. While generating beneficial effects on hyperglycemia, metformin also improves insulin resistance and corrects dyslipidemia in patients with T2D. These beneficial effects of metformin implicate a role for metformin in managing non-alcoholic fatty liver disease. As supported by the results from both human and animal studies, metformin improves hepatic steatosis and suppresses liver inflammation. Mechanistically, the beneficial effects of metformin on hepatic aspects are mediated through both adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. In addition, metformin is generally safe and may also benefit patients with other chronic liver diseases.

  9. Noninvasive metabolic imaging of engineered 3D human adipose tissue in a perfusion bioreactor.

    Directory of Open Access Journals (Sweden)

    Andrew Ward

    Full Text Available The efficacy and economy of most in vitro human models used in research is limited by the lack of a physiologically-relevant three-dimensional perfused environment and the inability to noninvasively quantify the structural and biochemical characteristics of the tissue. The goal of this project was to develop a perfusion bioreactor system compatible with two-photon imaging to noninvasively assess tissue engineered human adipose tissue structure and function in vitro. Three-dimensional (3D vascularized human adipose tissues were engineered in vitro, before being introduced to a perfusion environment and tracked over time by automated quantification of endogenous markers of metabolism using two-photon excited fluorescence (TPEF. Depth-resolved image stacks were analyzed for redox ratio metabolic profiling and compared to prior analyses performed on 3D engineered adipose tissue in static culture. Traditional assessments with H&E staining were used to qualitatively measure extracellular matrix generation and cell density with respect to location within the tissue. The distribution of cells within the tissue and average cellular redox ratios were different between static and perfusion cultures, while the trends of decreased redox ratio and increased cellular proliferation with time in both static and perfusion cultures were similar. These results establish a basis for noninvasive optical tracking of tissue structure and function in vitro, which can be applied to future studies to assess tissue development or drug toxicity screening and disease progression.

  10. Noninvasive metabolic imaging of engineered 3D human adipose tissue in a perfusion bioreactor.

    Science.gov (United States)

    Ward, Andrew; Quinn, Kyle P; Bellas, Evangelia; Georgakoudi, Irene; Kaplan, David L

    2013-01-01

    The efficacy and economy of most in vitro human models used in research is limited by the lack of a physiologically-relevant three-dimensional perfused environment and the inability to noninvasively quantify the structural and biochemical characteristics of the tissue. The goal of this project was to develop a perfusion bioreactor system compatible with two-photon imaging to noninvasively assess tissue engineered human adipose tissue structure and function in vitro. Three-dimensional (3D) vascularized human adipose tissues were engineered in vitro, before being introduced to a perfusion environment and tracked over time by automated quantification of endogenous markers of metabolism using two-photon excited fluorescence (TPEF). Depth-resolved image stacks were analyzed for redox ratio metabolic profiling and compared to prior analyses performed on 3D engineered adipose tissue in static culture. Traditional assessments with H&E staining were used to qualitatively measure extracellular matrix generation and cell density with respect to location within the tissue. The distribution of cells within the tissue and average cellular redox ratios were different between static and perfusion cultures, while the trends of decreased redox ratio and increased cellular proliferation with time in both static and perfusion cultures were similar. These results establish a basis for noninvasive optical tracking of tissue structure and function in vitro, which can be applied to future studies to assess tissue development or drug toxicity screening and disease progression.

  11. DEPTOR-mTOR Signaling Is Critical for Lipid Metabolism and Inflammation Homeostasis of Lymphocytes in Human PBMC Culture

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    Qi-bing Xie

    2017-01-01

    Full Text Available Abnormal immune response of the body against substances and tissues causes autoimmune diseases, such as polymyositis, dermatomyositis, and rheumatoid arthritis. Irregular lipid metabolism and inflammation may be a significant cause of autoimmune diseases. Although much progress has been made, mechanisms of initiation and proceeding of metabolic and inflammatory regulation in autoimmune disease have not been well-defined. And novel markers for the detection and therapy of autoimmune disease are urgent. mTOR signaling is a central regulator of extracellular metabolic and inflammatory processes, while DEP domain-containing mTOR-interacting protein (DEPTOR is a natural inhibitor of mTOR. Here, we report that overexpression of DEPTOR reduces mTORC1 activity in lymphocytes of human peripheral blood mononuclear cells (PBMCs. Combination of DEPTOR overexpression and mTORC2/AKT inhibitors effectively inhibits lipogenesis and inflammation in lymphocytes of PBMC culture. Moreover, DEPTOR knockdown activates mTORC1 and increases lipogenesis and inflammations. Our findings provide a deep insight into the relationship between lipid metabolism and inflammations via DEPTOR-mTOR pathway and imply that DEPTOR-mTOR in lymphocytes of PBMC culture has the potential to be as biomarkers for the detection and therapies of autoimmune diseases.

  12. DEPTOR-mTOR Signaling Is Critical for Lipid Metabolism and Inflammation Homeostasis of Lymphocytes in Human PBMC Culture

    Science.gov (United States)

    Liang, Yan; Yang, Yuan

    2017-01-01

    Abnormal immune response of the body against substances and tissues causes autoimmune diseases, such as polymyositis, dermatomyositis, and rheumatoid arthritis. Irregular lipid metabolism and inflammation may be a significant cause of autoimmune diseases. Although much progress has been made, mechanisms of initiation and proceeding of metabolic and inflammatory regulation in autoimmune disease have not been well-defined. And novel markers for the detection and therapy of autoimmune disease are urgent. mTOR signaling is a central regulator of extracellular metabolic and inflammatory processes, while DEP domain-containing mTOR-interacting protein (DEPTOR) is a natural inhibitor of mTOR. Here, we report that overexpression of DEPTOR reduces mTORC1 activity in lymphocytes of human peripheral blood mononuclear cells (PBMCs). Combination of DEPTOR overexpression and mTORC2/AKT inhibitors effectively inhibits lipogenesis and inflammation in lymphocytes of PBMC culture. Moreover, DEPTOR knockdown activates mTORC1 and increases lipogenesis and inflammations. Our findings provide a deep insight into the relationship between lipid metabolism and inflammations via DEPTOR-mTOR pathway and imply that DEPTOR-mTOR in lymphocytes of PBMC culture has the potential to be as biomarkers for the detection and therapies of autoimmune diseases. PMID:28349073

  13. Differences in gluten metabolism among healthy volunteers, coeliac disease patients and first-degree relatives.

    Science.gov (United States)

    Caminero, Alberto; Nistal, Esther; Herrán, Alexandra R; Pérez-Andrés, Jénifer; Ferrero, Miguel A; Vaquero Ayala, Luis; Vivas, Santiago; Ruiz de Morales, José M G; Albillos, Silvia M; Casqueiro, Francisco Javier

    2015-10-28

    Coeliac disease (CD) is an immune-mediated enteropathy resulting from exposure to gluten in genetically predisposed individuals. Gluten proteins are partially digested by human proteases generating immunogenic peptides that cause inflammation in patients carrying HLA-DQ2 and DQ8 genes. Although intestinal dysbiosis has been associated with patients with CD, bacterial metabolism of gluten has not been studied in depth thus far. The aim of this study was to analyse the metabolic activity of intestinal bacteria associated with gluten intake in healthy individuals, CD patients and first-degree relatives of CD patients. Faecal samples belonging to twenty-two untreated CD patients, twenty treated CD patients, sixteen healthy volunteers on normal diet, eleven healthy volunteers on gluten-free diet (GFD), seventy-one relatives of CD patients on normal diet and sixty-nine relatives on GFD were tested for several proteolytic activities, cultivable bacteria involved in gluten metabolism, SCFA and the amount of gluten in faeces. We detected faecal peptidasic activity against the gluten-derived peptide 33-mer. CD patients showed differences in faecal glutenasic activity (FGA), faecal tryptic activity (FTA), SCFA and faecal gluten content with respect to healthy volunteers. Alterations in specific bacterial groups metabolising gluten such as Clostridium or Lactobacillus were reported in CD patients. Relatives showed similar parameters to CD patients (SCFA) and healthy volunteers (FTA and FGA). Our data support the fact that commensal microbial activity is an important factor in the metabolism of gluten proteins and that this activity is altered in CD patients.

  14. Metabolic syndrome in human immunodeficiency virus positive patients

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    Sarita Bajaj

    2013-01-01

    Full Text Available Aims and Objectives : To assess the prevalence of metabolic syndrome (MetS in human immunodeficiency virus (HIV positive patients. Prevalence of MetS was compared in patients who were not on highly active antiretroviral therapy (HAART to patients who were on HAART. Materials and Methods: Seventy HIV positive cases were studied. Pregnant and lactating women, patients on drugs other than HAART known to cause metabolic abnormalities and those having diabetes or hypertension were excluded. Cases were evaluated for MetS by using National Cholesterol Education Program Adult Treatment Panel-III. Results: 47 cases were on HAART and 23 cases were not on HAART. Fasting Blood Glucose ≥100 mg/dl was present in 28.6% cases, out of whom 27.7% were on HAART and 30.4% were not on HAART (P = 0.8089. 12.9% cases had BP ≥130/≥85 mm Hg, out of whom 14.9% were on HAART and 8.7% were not on HAART (P = 0.4666. 42.9% cases had TG ≥150 mg/dl, out of whom 44.7% were on HAART and 39.1% were not on HAART (P = 0.6894. HDL cholesterol was low (males <40 mg/dl, females <50 mg/dl in 50% cases, out of whom 55.3% were on HAART and 39.1% were not on HAART (P = 0.2035. Conclusions: Prevalence of MetS was 20%. Majority of patients had only one component of MetS (32.9%. Low HDL was present in 50%, followed by raised triglycerides in 42.9%. Waist circumference was not increased in any of the patients. There was no statistically significant difference between those on HAART and those not on HAART in distribution of risk factors and individual components of MetS.

  15. Glucose Metabolism of Human Prostate Cancer Mouse Xenografts

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    Hossein Jadvar

    2005-04-01

    Full Text Available We hypothesized that the glucose metabolism of prostate cancer is modulated by androgen. We performed in vivo biodistribution and imaging studies of [F-18] fluorodeoxyglucose (FDG accumulation in androgen-sensitive (CWR-22 and androgen-independent (PC-3 human prostate cancer xenografts implanted in castrated and noncastrated male athymic mice. The growth pattern of the CWR-22 tumor was best approximated by an exponential function (tumor size in mm3 = 14.913 e0.108 × days, R2 = .96, n = 5. The growth pattern of the PC-3 tumor was best approximated by a quadratic function (tumor size in mm3 = 0.3511 × days2 + 49.418 × day −753.33, R2 = .96, n = 3. The FDG accumulation in the CWR-22 tumor implanted in the castrated mice was significantly lower, by an average of 55%, in comparison to that implanted in the noncastrated host (1.27 vs. 2.83, respectively, p < .05. The 3-week maximal standardized uptake value (SUVmax was 0.99 ± 0.43 (mean ± SD for CWR-22 and 1.21 ± 0.32 for PC-3, respectively. The 5-week SUVmax was 1.22 ± 0.08 for CWR-22 and 1.35 ± 0.17 for PC-3, respectively. The background muscle SUVmax was 0.53 ± 0.11. Glucose metabolism was higher in the PC-3 tumor than in the CWR-22 tumor at both the 3-week (by 18% and the 5-week (by 9.6% micro-PET imaging sessions. Our results support the notions that FDG PET may be useful in the imaging evaluation of response to androgen ablation therapy and in the early prediction of hormone refractoriness in men with metastatic prostate cancer.

  16. A conceptual disease model for adult Pompe disease Inherited metabolic diseases

    NARCIS (Netherlands)

    T.A. Kanters (Tim A.); E. Orlewska (William Ken); M.P.M.H. Rutten-van Mölken (Maureen); M.E. Kruijshaar (Michelle); D. Güngör (Deniz); A.T. van der Ploeg (Ans); L. van Hakkaart-van Roijen (Leona)

    2015-01-01

    textabstractBackground: Studies in orphan diseases are, by nature, confronted with small patient populations, meaning that randomized controlled trials will have limited statistical power. In order to estimate the effectiveness of treatments in orphan diseases and extrapolate effects into the future

  17. In vitro metabolism of genistein and tangeretin by human and murine cytochrome p450s

    DEFF Research Database (Denmark)

    Breinholt, Vibeke; Rasmussen, Salka; Brøsen, Kim

    2003-01-01

    Recombinant cytochrome P450 (CYP) 1A2, 3A4, 2C9 or 2D6 enzymes obtained from Escherichia coli and human liver microsomes samples were used to investigate the ability of human CYP enzymes to metabolize the two dietary flavonoids, genistein and tangeretin. Analysis of the metabolic profile from...

  18. Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases.

    Science.gov (United States)

    Spite, Matthew; Clària, Joan; Serhan, Charles N

    2014-01-07

    Inflammation is associated with the development of diseases characterized by altered nutrient metabolism. Although an acute inflammatory response is host-protective and normally self-limited, chronic low-grade inflammation associated with metabolic diseases is sustained and detrimental. The resolution of inflammation involves the termination of neutrophil recruitment, counterregulation of proinflammatory mediators, stimulation of macrophage-mediated clearance, and tissue remodeling. Specialized proresolving lipid mediators (SPMs)-resolvins, protectins, and maresins-are novel autacoids that resolve inflammation, protect organs, and stimulate tissue regeneration. Here, we review evidence that the failure of resolution programs contributes to metabolic diseases and that SPMs may play pivotal roles in their resolution.

  19. Effects of Soy on Metabolic Biomarkers of Cardiovascular Disease in Elderly Women with the Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Afsaneh Bakhtiary

    2010-09-01

    Full Text Available Objective: To ascertain the effects of soy [in the forms of Textured Soy Protein (TSP and soy-nut] onlipid profiles, apolipoproteins, inflammatory and prothrombotic markers and blood pressure in elderlywomen with the metabolic syndrome.Materials and methods: The study is a 12-week parallel randomized controlled trial that was conductedin rural health centres of Babol, Iran. The participants were 75 women 60-70 years old with the metabolicsyndrome who were randomized to one of the three groups of soy-nut (35g/d, TSP (35g/d and control.Blood pressure and blood biochemical markers were measured at baseline and at the end of the studyincluding, triglyceride, cholesterol, HDL-C, LDL-C, VLDL-C, ApoB100, ApoAI, CRP and fibrinogen.Results: The soy-nut improved significantly LDL-C, VLDL-C and Apo B100 (P<0.05 while fewer improvementsbut significant were observed in these variables in the TSP group only when compared with themean changes from the baseline (P<0.001. Similar result was found for Apo AI in the treatment groups(P<0.01. Serum total cholesterol decreased significantly in the treatment groups compared with controlgroup (P<0.005. The differences from control for triglyceride, HDL-C, fibrinogen, CRP and bloodpressure were not significant.Conclusion: Both forms of soy while improved lipids profiles the soy-nut contribution was more to thisimprovement than the TSP. Therefore, moderate daily intake of soy may be a safe, cheap and practicalmethod to improve cardiovascular disease risk and also reduce the need for medical treatment.

  20. METABOLISM OF 3 PHARMACOLOGICALLY ACTIVE-DRUGS IN ISOLATED HUMAN AND RAT HEPATOCYTES - ANALYSIS OF INTERSPECIES VARIABILITY AND COMPARISON WITH METABOLISM IN-VIVO

    NARCIS (Netherlands)

    SANDKER, GW; VOS, RME; DELBRESSINE, LPC; SLOOFF, MJH; MEIJER, DKF; GROOTHUIS, GMM

    1994-01-01

    1. The metabolism of the three drugs (Org GB 94, Org 3770 and Org OD 14) was studied in isolated human and rat hepatocytes. The metabolic profiles in rat and human hepatocytes were compared with the available in vivo data in both species. 2. All three drugs were metabolized extensively under the con

  1. Therapeutic Targets of Triglyceride Metabolism as Informed by Human Genetics.

    Science.gov (United States)

    Bauer, Robert C; Khetarpal, Sumeet A; Hand, Nicholas J; Rader, Daniel J

    2016-04-01

    Human genetics has contributed to the development of multiple drugs to treat hyperlipidemia and coronary artery disease (CAD), most recently including antibodies targeting PCSK9 to reduce LDL cholesterol. Despite these successes, a large burden of CAD remains. Genetic and epidemiological studies have suggested that circulating triglyceride (TG)-rich lipoproteins (TRLs) are a causal risk factor for CAD, presenting an opportunity for novel therapeutic strategies. We discuss recent unbiased human genetics testing, including genome-wide association studies (GWAS) and whole-genome or -exome sequencing, that have identified the lipoprotein lipase (LPL) and hepatic lipogenesis pathways as important mechanisms in the regulation of circulating TRLs. Further strengthening the causal relationship between TRLs and CAD, findings such as these may provide novel targets for much-needed potential therapeutic interventions. Copyright © 2016. Published by Elsevier Ltd.

  2. Human lagochilascariasis-A rare helminthic disease.

    Directory of Open Access Journals (Sweden)

    Dulcinea Maria Barbosa Campos

    2017-06-01

    Full Text Available Lagochilascariasis is a parasitic disease caused by a helminth of the order Ascaroidea, genus Lagochilascaris that comprises 6 species, among which only Lagochilascaris minor Leiper, 1909, is implicated in the human form of the disease. It is remarkable that the majority of cases of human lagochilascariasis in the Americas have been reported in Brazil. The natural definitive hosts of this parasite seem to be wild felines and canines. Lagochilascariasis is mostly a chronic human disease that can persist for several years, in which the parasite burrows into the subcutaneous tissues of the neck, paranasal sinuses, and mastoid. L. minor exhibits remarkable ability to migrate through the tissues of its hosts, destroying even bone tissue. Fatal cases have been described in which the parasite was found in the lungs or central nervous system. Treatment is often palliative, with recurrence of lesions. This paper summarizes the main features of the disease and its etiologic agent, including prevalence, life cycle, clinical course, and treatment.

  3. Heartworm disease in animals and humans.

    Science.gov (United States)

    McCall, John W; Genchi, Claudio; Kramer, Laura H; Guerrero, Jorge; Venco, Luigi

    2008-01-01

    Heartworm disease due to Dirofilaria immitis continues to cause severe disease and even death in dogs and other animals in many parts of the world, even though safe, highly effective and convenient preventatives have been available for the past two decades. Moreover, the parasite and vector mosquitoes continue to spread into areas where they have not been reported previously. Heartworm societies have been established in the USA and Japan and the First European Dirofilaria Days (FEDD) Conference was held in Zagreb, Croatia, in February of 2007. These organizations promote awareness, encourage research and provide updated guidelines for the diagnosis, treatment and prevention of heartworm disease. The chapter begins with a review of the biology and life cycle of the parasite. It continues with the prevalence and distribution of the disease in domestic and wild animals, with emphasis on more recent data on the spreading of the disease and the use of molecular biology techniques in vector studies. The section on pathogenesis and immunology also includes a discussion of the current knowledge of the potential role of the Wolbachia endosymbiont in inflammatory and immune responses to D. immitis infection, diagnostic use of specific immune responses to the bacteria, immunomodulatory activity and antibiotic treatment of infected animals. Canine, feline and ferret heartworm disease are updated with regard to the clinical presentation, diagnosis, prevention, therapy and management of the disease, with special emphasis on the recently described Heartworm Associated Respiratory Disease (HARD) Syndrome in cats. The section devoted to heartworm infection in humans also includes notes on other epizootic filariae, particularly D. repens in humans in Europe. The chapter concludes with a discussion on emerging strategies in heartworm treatment and control, highlighting the potential role of tetracycline antibiotics in adulticidal therapy.

  4. Metabolic profiling of cholesterol and sex steroid hormones to monitor urological diseases.

    Science.gov (United States)

    Moon, Ju-Yeun; Choi, Man Ho; Kim, Jayoung

    2016-10-01

    Cholesterol and sex steroid hormones including androgens and estrogens play a critical role in the development and progression of urological diseases such as prostate cancer. This disease remains the most commonly diagnosed malignant tumor in men and is the leading cause of death from different cancers. Attempts to understand the role of cholesterol and steroid metabolism in urological diseases have been ongoing for many years, but despite this, our mechanistic and translational understanding remains elusive. In order to further evaluate the problem, we have taken an interest in metabolomics; a discipline dedicated to the systematic study of biologically active metabolites in cells, tissues, hair and biofluids. Recently, we provided evidence that a quantitative measurement of cholesterol and sex steroid metabolites can be successfully achieved using hair of human and mouse models. The overall goal of this short review article is to introduce current metabolomic technologies for the quantitative biomarker assay development and also to provide new insight into understanding the underlying mechanisms that trigger the pathological condition. Furthermore, this review will place a particular emphasis on how to prepare biospecimens (e.g., hair fiber), quantify molecular profiles and assess their clinical significance in various urological diseases.

  5. Functions of NOD-like receptors (NLRs in human diseases

    Directory of Open Access Journals (Sweden)

    Yifei eZhong

    2013-10-01

    Full Text Available Nucleotide-binding and oligomerization domain (NOD-like receptors (NLRs are highly conserved cytosolic pattern recognition receptors that perform critical functions in surveying the intracellular environment for the presence of infection, noxious substances, and metabolic perturbations. Sensing of these danger signals by NLRs leads to their oligomerization into large macromolecular scaffolds and the rapid deployment of effector signaling cascades to restore homeostasis. While some NLRs operate by recruiting and activating inflammatory caspases into inflammasomes, others trigger inflammation via alternative routes including the NF-κB, MAPK and IRF pathways. The critical role of NLRs in development and physiology is demonstrated by their clear implications in human diseases. Mutations in the genes encoding NLRP3 or NLRP12 lead to hereditary periodic fever syndromes, while mutations in CARD15 that encodes NOD2 are linked to Crohn’s disease or Blau’s syndrome. Genome-wide association studies (GWAS have identified a number of risk alleles encompassing NLR genes in a host of diseases including allergic rhinitis, multiple sclerosis, inflammatory bowel disease, asthma, multi-bacillary leprosy, vitiligo, early-onset menopause, and bone density loss in elderly women. Animal models have allowed the characterization of underlying effector mechanisms in a number of cases. In this review, we highlight the functions of NLRs in health and disease and discuss how the characterization of their molecular mechanisms provides new insights into therapeutic strategies for the management of inflammatory pathologies.

  6. Lysophosphatidic acid metabolism and elimination in cardiovascular disease

    Science.gov (United States)

    Salous, Abdelghaffar Kamal

    The bioactive lipids lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are present in human and mouse plasma at a concentration of ~0.1-1 microM and regulate physiological and pathophysiological processes in the cardiovascular system including atherothrombosis, intimal hyperplasia, and immune function, edema formation, and permeability. PPAP2B, the gene encoding LPP3, a broad activity integral membrane enzyme that terminates LPA actions in the vasculature, has a single nucleotide polymorphism that been recently associated with coronary artery disease risk. The synthesis and signaling of LPA and S1P in the cardiovascular system have been extensively studied but the mechanisms responsible for their elimination are less well understood. The broad goal of this research was to examine the role of LPP3 in the termination of LPA signaling in models of cardiovascular disease involving vascular wall cells, investigate the role of LPP3 in the elimination of plasma LPA, and further characterize the elimination of plasma LPA. The central hypothesis is that LPP3 plays an important role in attenuating the pathological responses to LPA signaling and that it mediates the elimination of exogenously applied bioactive lipids from the plasma. These hypotheses were tested using molecular biological approaches, in vitro studies, synthetic lysophospholipid mimetics, modified surgical procedures, and mass spectrometry assays. My results indicated that LPP3 played a critical role in attenuating LPA signaling mediating the pathological processes of intimal hyperplasia and vascular leak in mouse models of disease. Additionally, enzymatic inactivation of lysophospholipids by LPP and PLA enzymes in the plasma was not a primary mechanism for the rapid elimination of plasma LPA and S1P. Instead, evidence strongly suggested a transcellular uptake mechanism by hepatic non-parenchymal cells as the predominant mechanism for elimination of these molecules. These results support a model in

  7. Chronic obstructive pulmonary disease and the metabolic syndrome: Consequences of a dual threat

    OpenAIRE

    Dukhabandhu Naik; Anjali Joshi; Thomas Vizhalil Paul; Nihal Thomas

    2014-01-01

    The metabolic syndrome is found to be more frequent in chronic obstructive pulmonary disease (COPD). The presence of inflammatory markers in circulation, sputum, and broncho-alveolar fluid suggest systemic inflammation is one of the potential mechanisms responsible for both COPD and metabolic syndrome. Physical inactivity, skeletal muscle dysfunction, hypogonadism, and steroid use are also important causes of the metabolic syndrome in COPD. Obesity and insulin resistance is found to be more c...

  8. Pyrroline-5-carboxylate synthase and proline biosynthesis: From osmotolerance to rare metabolic disease

    Science.gov (United States)

    Pérez-Arellano, Isabel; Carmona-Álvarez, Francisco; Martínez, Ana I; Rodríguez-Díaz, Jesús; Cervera, Javier

    2010-01-01

    Pyrroline-5-carboxylate synthase (P5CS) is a bifunctional enzyme that exhibits glutamate kinase (GK) and γ-glutamyl phosphate reductase (GPR) activities. The enzyme is highly relevant in humans because it belongs to a combined route for the interconversion of glutamate, ornithine and proline. The deficiency of P5CS activity in humans is associated with a rare, inherited metabolic disease. It is well established that some bacteria and plants accumulate proline in response to osmotic stress. The alignment of P5CSs from different species and analysis of the solved structures of GK and GPR reveal high sequence and structural conservation. The information acquired from different mutant enzymes with increased osmotolerant properties, together with the position of the insertion found in the longer human isoform, permit the delimitation of the regulatory site of GK and P5CS and the proposal of a model of P5CS architecture. Additionally, the GK moiety of the human enzyme has been modeled and the known clinical mutations and polymorphisms have been mapped. PMID:20091669

  9. Unsolved issues related to human mitochondrial diseases.

    Science.gov (United States)

    Lombès, Anne; Auré, Karine; Bellanné-Chantelot, Christine; Gilleron, Mylène; Jardel, Claude

    2014-05-01

    Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed. Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.

  10. Impact of maternal metabolic abnormalities in pregnancy on human milk and subsequent infant metabolic development: methodology and design

    Directory of Open Access Journals (Sweden)

    Hamilton Jill K

    2010-10-01

    Full Text Available Abstract Background Childhood obesity is on the rise and is a major risk factor for type 2 diabetes later in life. Recent evidence indicates that abnormalities that increase risk for diabetes may be initiated early in infancy. Since the offspring of women with diabetes have an increased long-term risk for obesity and type 2 diabetes, the impact of maternal metabolic abnormalities on early nutrition and infant metabolic trajectories is of considerable interest. Human breast milk, the preferred food during infancy, contains not only nutrients but also an array of bioactive substances including metabolic hormones. Nonetheless, only a few studies have reported concentrations of metabolic hormones in human milk specifically from women with metabolic abnormalities. We aim to investigate the impact of maternal metabolic abnormalities in pregnancy on human milk hormones and subsequently on infant development over the first year of life. The objective of this report is to present the methodology and design of this study. Methods/Design The current investigation is a prospective study conducted within ongoing cohort studies of women and their offspring. Pregnant women attending outpatient obstetrics clinics in Toronto, Canada were recruited. Between April 2009 and July 2010, a total of 216 pregnant women underwent a baseline oral glucose tolerance test and provided medical and lifestyle history. Follow-up visits and telephone interviews are conducted and expected to be completed in October 2011. Upon delivery, infant birth anthropometry measurements and human breast milk samples are collected. At 3 and 12 months postpartum, mothers and infants are invited for follow-up assessments. Interim telephone interviews are conducted during the first year of offspring life to characterize infant feeding and supplementation behaviors. Discussion An improved understanding of the link between maternal metabolic abnormalities in pregnancy and early infant nutrition may

  11. The role of formins in human disease.

    Science.gov (United States)

    DeWard, Aaron D; Eisenmann, Kathryn M; Matheson, Stephen F; Alberts, Arthur S

    2010-02-01

    Formins are a conserved family of proteins that play key roles in cytoskeletal remodeling. They nucleate and processively elongate non-branched actin filaments and also modulate microtubule dynamics. Despite their significant contributions to cell biology and development, few studies have directly implicated formins in disease pathogenesis. This review highlights the roles of formins in cell division, migration, immunity, and microvesicle formation in the context of human disease. In addition, we discuss the importance of controlling formin activity and protein expression to maintain cell homeostasis.

  12. Human papillomavirus-associated diseases and cancers

    Institute of Scientific and Technical Information of China (English)

    Lan Yang; Jianbo Zhu Co-first author; Xiaoyue Song; Yan Qi; Xiaobin Cui; Feng Li 

    2015-01-01

    Human papilomaviruses (HPVs) have been detected in cervical cancer cels and skin papiloma cels, which have a variety of types, including low-risk and high-risk types. HPV genome replication requires the host cel’s DNA synthesis machinery, and HPVs encode proteins that maintain diferentiated epithelial cels in a replication-competent state. HPV types are tissue-specific and generaly produce diferent types of le-sions, either benign or malignant. This review examines diferent HPV types and their associated diseases and presents therapeutic options for the treatment of HPV-positive diseases.

  13. Disease of the Sultans: metabolic syndrome in Ottoman dynasty.

    Science.gov (United States)

    Dağdelen, Selçuk; Erbaş, Tomris

    2010-06-01

    Metabolic syndrome is generally considered as a complication of modernity. Here we searched for the presence of metabolic syndrome components among the Ottoman emperors who lived between 1258 and 1926. Collections of historical archives, which were published as books specifically about morbidity and mortality of Ottoman emperors were reviewed to diagnose metabolic syndrome according to modified criteria by American College of Endocrinology and American Association of Clinical Endocrinologists. Nineteen of 36 dynasty members (53%) had fatal or non-fatal cardiovascular events. Twenty-nine of the dynasty (81%) members were either depicted as truncal obese or reported to have obesity. Thirteen emperors (36%) satisfied diagnostic criteria for metabolic syndrome, retrospectively. Overall, 42% of non-commanding emperors, but 26% of commanding-emperors (who were assumed to be athletically grown and physically more active) were found to have metabolic syndrome (p=0.553). We suggest firstly here that sedentary palace lifestyle exacerbated metabolic syndrome in Ottoman dynasty especially in elderly members, thereafter complicated by cardiovascular events, even in pre-modern era.

  14. Dissecting cis regulation of gene expression in human metabolic tissues.

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    Radu Dobrin

    Full Text Available Complex diseases such as obesity and type II diabetes can result from a failure in multiple organ systems including the central nervous system and tissues involved in partitioning and disposal of nutrients. Studying the genetics of gene expression in tissues that are involved in the development of these diseases can provide insights into how these tissues interact within the context of disease. Expression quantitative trait locus (eQTL studies identify mRNA expression changes linked to proximal genetic signals (cis eQTLs that have been shown to affect disease. Given the high impact of recent eQTL studies, it is important to understand what role sample size and environment plays in identification of cis eQTLs. Here we show in a genotyped obese human population that the number of cis eQTLs obey precise scaling laws as a function of sample size in three profiled tissues, i.e. omental adipose, subcutaneous adipose and liver. Also, we show that genes (or transcripts with cis eQTL associations detected in a small population are detected at approximately 90% rate in the largest population available for our study, indicating that genes with strong cis acting regulatory elements can be identified with relatively high confidence in smaller populations. However, by increasing the sample size we allow for better detection of weaker and more distantly located cis-regulatory elements. Yet, we determined that the number of tissue specific cis eQTLs saturates in a modestly sized cohort while the number of cis eQTLs common to all tissues fails to reach a maximum value. Understanding the power laws that govern the number and specificity of eQTLs detected in different tissues, will allow a better utilization of genetics of gene expression to inform the molecular mechanism underlying complex disease traits.

  15. Understanding Postprandial Inflammation and Its Relationship to Lifestyle Behaviour and Metabolic Diseases

    OpenAIRE

    Boudewijn Klop; Proctor, Spencer D.; Mamo, John C; Botham, Kathleen M; Manuel Castro Cabezas

    2012-01-01

    Postprandial hyperlipidemia with accumulation of remnant lipoproteins is a common metabolic disturbance associated with atherosclerosis and vascular dysfunction, particularly during chronic disease states such as obesity, the metabolic syndrome and, diabetes. Remnant lipoproteins become attached to the vascular wall, where they can penetrate intact endothelium causing foam cell formation. Postprandial remnant lipoproteins can activate circulating leukocytes, upregulate the expression of endot...

  16. Metabolic adaptations in models of fatty liver disease : Of mice and math

    NARCIS (Netherlands)

    Hijmans, Brenda

    2017-01-01

    The increasing incidence of overweight is accompanied by a plethora of medical symptoms together called the metabolic syndrome. Non-alcoholic fatty liver disease, characterized by persistent storage of lipids in the liver, is regarded as the hepatic component of the metabolic syndrome. An imbalance

  17. The interaction of hepatic lipid and glucose metabolism in liver diseases

    NARCIS (Netherlands)

    Bechmann, Lars P.; Hannivoort, Rebekka A.; Gerken, Guido; Hotamisligil, Goekhan S.; Trauner, Michael; Canbay, Ali

    It is widely known that the liver is a central organ in lipogenesis, gluconeogenesis and cholesterol metabolism. However, over the last decades, a variety of pathological conditions highlighted the importance of metabolic functions within the diseased liver. As observed in Western societies, an