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Zoppe M.,CNR Institute of Clinical Physiology
Nature Methods | Year: 2017

Cells are minute - typically too small to be seen by the human eye. Even so, the cellular world encompasses a range of scales, from roughly a tenth of a nanometer (10-10 m) to a millimeter (10-3 m) or larger, spanning seven orders of magnitude or more. Because they are so far from our experience, it is difficult for us to envision such scales. To help our imagination grasp such dimensions, I propose the adoption of a 'perceptive scale' that can facilitate a more direct experience of cellular sizes. From this, as I argue below, will stem a new perception also of biological shape, cellular space and dynamic processes. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

Zoccali C.,CNR Institute of Clinical Physiology
Nature Reviews Nephrology | Year: 2017

The accurate definition and staging of chronic kidney disease (CKD) is one of the major achievements of modern nephrology. Intensive research is now being undertaken to unravel the risk factors and pathophysiologic underpinnings of this disease. In particular, the relationships between the kidney and other organs have been comprehensively investigated in experimental and clinical studies in the last two decades. Owing to technological and analytical limitations, these links have been studied with a reductionist approach focusing on two organs at a time, such as the heart and the kidney or the bone and the kidney. Here, we discuss studies that highlight the complex and systemic nature of CKD. Energy balance, innate immunity and neuroendocrine signalling are highly integrated biological phenomena. The diseased kidney disrupts such integration and generates a high-risk phenotype with a clinical profile encompassing inflammation, protein–energy wasting, altered function of the autonomic and central nervous systems and cardiopulmonary, vascular and bone diseases. A systems biology approach to CKD using omics techniques will hopefully enable in-depth study of the pathophysiology of this systemic disease, and has the potential to unravel critical pathways that can be targeted for CKD prevention and therapy. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Poliseno L.,CNR Institute of Clinical Physiology | Poliseno L.,CNR Institute of Neuroscience | Pandolfi P.P.,Beth Israel Deaconess Medical Center
Methods | Year: 2015

In multiple human cancer types, a close link exists between the expression levels of Phosphatase and Tensin Homolog deleted on chromosome 10 (PTEN) and its oncosuppressive activities. Therefore, an in depth understanding of the molecular mechanisms by which PTEN expression is modulated is crucial in order to achieve a comprehensive knowledge of its biological roles. In recent years, the competition between PTEN mRNA and other RNAs for shared microRNA molecules has emerged as one such mechanism and has brought into focus the coding-independent activities of PTEN and other mRNAs. In this review article, we examine the competing endogenous RNA (ceRNA) partners of PTEN that have been identified so far. We also discuss how PTEN-centered ceRNA networks can contribute to a deeper understanding of PTEN function and tumorigenesis. © 2015.

Del Turco S.,CNR Institute of Clinical Physiology | Basta G.,CNR Institute of Clinical Physiology
BioFactors | Year: 2012

Advanced glycation endproducts (AGEs) are a group of modified molecular species formed by nonenzymatic reactions between the aldehydic group of reducing sugars with proteins, lipids, or nucleic acids. Formation and accumulation of AGEs are related to the aging process and are accelerated in diabetes. AGEs are generated in hyperglycemia, but their production also occurs in settings characterized by oxidative stress and inflammation. These species promote vascular damage and acceleration of atherosclerotic plaque progression mainly through two mechanisms: directly, altering the functional properties of vessel wall extracellular matrix molecules, or indirectly, through activation of cell receptor-dependent signaling. Interaction between AGEs and the key receptor for AGEs (RAGE), a transmembrane signaling receptor which is present in all cells relevant to atherosclerosis, alters cellular function, promotes gene expression, and enhances the release of proinflammatory molecules. The importance of the AGE-RAGE interaction and downstream pathways, leading to vessel wall injury and plaque development, has been amply established in animal studies. Moreover, the deleterious link of AGEs with diabetic vascular complications has been suggested in many human studies. Blocking the vicious cycle of AGE-RAGE axis signaling may be essential in controlling and preventing cardiovascular complications. In this article, we review the pathogenetic role of AGEs in the development, progression and instability of atherosclerosis, and the potential targets of this biological system for the prevention and treatment of cardiovascular disease. © 2012 International Union of Biochemistry and Molecular Biology, Inc.

Iozzo P.,CNR Institute of Clinical Physiology
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2010

There is convincing evidence that alterations in myocardial substrate use play an important role in the normal and diseased heart. In this review, insights gained by using quantitative molecular imaging by positron emission tomography and magnetic resonance spectroscopy in the study of human myocardial metabolism will be discussed, and attention will be paid to the effects of nutrition, gender, aging, obesity, diabetes, cardiac hypertrophy, ischemia, and heart failure. The heart is an omnivore organ, relying on metabolic flexibility, which is compromised by the occurrence of defects in coronary flow reserve, insulin-mediated glucose disposal, and metabolic-mechanical coupling. Obesity, diabetes, and ischemic cardiomyopathy appear as states of high uptake and oxidation of fatty acids, that compromise the ability to utilize glucose under stimulated conditions, and lead to misuse of energy and oxygen, disturbing mechanical efficiency. Idiopathic heart failure is a complex disease frequently coexisting with diabetes, insulin resistance and hypertension, in which the end stage of metabolic toxicity manifests as severe mitochondrial disturbance, inability to utilize fatty acids, and ATP depletion. The current literature provides evidence that the primary events in the metabolic cascade outlined may originate in extra-cardiac organs, since fatty acid, glucose levels, and insulin action are mostly controlled by adipose tissue, skeletal muscle and liver, and that a broader vision of organ cross-talk may further our understanding of the primary and the adaptive events involved in metabolic heart toxicity. © 2009 Elsevier B.V. All rights reserved.

Del Ry S.,CNR Institute of Clinical Physiology
Peptides | Year: 2013

Natriuretic peptides are endogenous hormones released by the heart in response to myocardial stretch and overload. While atrial and brain natriuretic peptides (ANP, BNP) were immediately considered cardiac hormones and their role was well-characterized and defined in predicting risk in cardiovascular disease, evidence indicating the role of C-type natriuretic peptide (CNP) in cardiovascular regulation was slow to emerge until about 8 years ago. Since then, considerable literature on CNP and the cardiovascular system has been published; the aim of this review is to examine current literature relating to CNP and cardiovascular disease, in particular its role in heart failure (HF) and myocardial infarction (MI). This review retraces the fundamental steps in research that led understanding the role of CNP in HF and MI; from increased CNP mRNA expression and plasmatic concentrations in humans and in animal models, to detection of CNP expression in cardiomyocytes, to its evaluation in human leukocytes. The traditional view of CNP as an endothelial peptide has been surpassed by the results of many studies published in recent years, and while its physiological role is still under investigation, information is now available regarding its contribution to cardiovascular function. Taken together, these observations suggest that CNP and its specific receptor, NPR-B, can play a very important role in regulating cardiac hypertrophy and remodeling, indicating NPR-B as a new potential drug target for the treatment of cardiovascular disease. © 2013 Elsevier Inc. All rights reserved.

Salehi M.,University of Cincinnati | Gastaldelli A.,CNR Institute of Clinical Physiology | D'Alessio D.A.,University of Cincinnati | D'Alessio D.A.,Cincinnati Medical Center
Gastroenterology | Year: 2014

Background & Aims Postprandial glycemia excursions increase after gastric bypass surgery; this effect is even greater among patients with recurrent hypoglycemia. These patients also have increased postprandial levels of insulin and glucagon-like peptide 1 (GLP-1). We performed a clinical trial to determine the role of GLP-1 in postprandial glycemia in patients with hyperinsulinemic hypoglycemia syndrome after gastric bypass. Methods Nine patients with recurrent hypoglycemia after gastric bypass (H-GB), 7 patients who were asymptomatic after gastric bypass (A-GB), and 8 healthy control subjects underwent a mixed-meal tolerance test (350 kcal) using a dual glucose tracer method on 2 separate days. On 1 day they received continuous infusion of the GLP-1 receptor antagonist exendin (9-39) (Ex-9), and on the other day they received a saline control. Glucose kinetics and islet and gut hormone responses were measured before and after the meal. Results Infusion of Ex-9 corrected hypoglycemia in all patients with H-GB. The reduction in postprandial insulin secretion by Ex-9 was greater in the H-GB group than in the other groups (H-GB, 50% ± 8%; A-GB, 13% ± 10%; controls, 14% ± 10%) (P <.05). The meal-derived glucose appearance was significantly greater in subjects who had undergone gastric bypass compared to the controls and in the H-GB group compared to the A-GB group. Ex-9 shortened the time to reach peak meal-derived glucose appearance in all groups without a significant effect on overall glucose flux. Postprandial glucagon levels were higher among patients who had undergone gastric bypass than controls and increased with administration of Ex-9. Conclusions Hypoglycemia after gastric bypass can be corrected by administration of a GLP-1 receptor antagonist, which might be used to treat this disorder. These findings are consistent with reports that increased GLP-1 activity contributes to hypoglycemia after gastric bypass., Number: NCT01803451. © 2014 by the AGA Institute.

Gastaldelli A.,CNR Institute of Clinical Physiology
Diabetes Research and Clinical Practice | Year: 2011

In the natural history of type 2 diabetes (T2DM), individuals progress from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to overt T2DM and this progression has been demonstrated in populations of diverse ethnic background. It is widely recognised that both insulin resistance and beta-cell dysfunction are important in the pathogenesis of glucose intolerance. In populations with a high prevalence of T2DM, insulin resistance is well established long before the development of any impairment in glucose homeostasis, particularly in subjects with ectopic fat accumulation. However, as long as the beta cell is able to secrete sufficient amounts of insulin to offset the severity of insulin resistance, glucose tolerance remains normal. This dynamic interaction between insulin secretion and insulin resistance is essential to the maintenance of NGT and interruption of this crosstalk between the beta cell and peripheral tissues results in the progressive deterioration of glucose homeostasis. In this paper the role of beta-cell function is reviewed, as well as the role of ectopic fat accumulation and insulin resistance in the development of type 2 diabetes. © 2011 Elsevier Ireland Ltd.

Capobianco E.,University of Miami | Capobianco E.,CNR Institute of Clinical Physiology | Lio' P.,University of Cambridge
Trends in Molecular Medicine | Year: 2013

Comorbidity represents an extremely complex domain of research. An individual entity, the patient, is the center of gravity of a system characterized by multiple, complex, and interrelated conditions, disorders, or diseases. Such complexity is influenced by uncertainty that is difficult to decipher and is proportional to the number of associated morbidities. Computational scientists usually provide meta-analysis studies aimed at integrating various types of evidence, but in our opinion they may help reformulate comorbidity by emphasizing, in particular, two aspects: (i) a systems approach, which allows for an ensemble view of comorbidity, and offers a model representation generalizable to multimorbidity; and (ii) a dynamic network inference approach, which is indicated for the analysis of links among morbidities and evaluation of risk. Notably, the main question remains whether such instruments suggest a shift of paradigm providing prospective impact on medical practice. We have identified in the simultaneous consideration of multiple dimensions linked to comorbidity complexity the rationale for such translation. © 2013 Elsevier Ltd.

Vecoli C.,CNR Institute of Clinical Physiology
Vitamins and Hormones | Year: 2014

Endothelial nitric oxide synthase (eNOS or NOS3), an enzyme constitutively expressed especially in endothelial cells, is largely responsible for nitric oxide (NO) bioavailability at the endothelial level. Alterations in endothelial-derived NO production have been associated with various diseases, and, in humans, can be genetically determined by the presence of different polymorphisms in the eNOS gene. To date, the most studied and functionally related polymorphisms are: Glu298Asp (rs1799983), - 786T/C (rs2070744), and the intron 4 variable number tandem repeat. Evidence supports a major role of these variants in increasing susceptibility to cardiovascular disease (such as coronary artery disease, myocardial infarction, hypertension, pre-eclampsia, and stroke) as well as in the onset of other complex diseases. © 2014 Elsevier Inc.

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