Mild exposure of RIN-5F β-cells to human islet amyloid polypeptide aggregates upregulates antioxidant enzymes via NADPH oxidase-RAGE: An hormetic stimulus

AbstractThe presence of amyloid aggregates of human islet amyloid polypeptide (hIAPP), a hallmark of type 2 diabetes, contributes to pancreatic β-cell impairment, where oxidative stress plays a key role. A contribution of NADPH oxidase to reactive oxygen species (ROS) generation after cell exposure to micromolar concentrations of hIAPP aggregates has been suggested. However, little is known about β-cells exposure to lower amounts of hIAPP aggregates, similar to those found in human pancreas. Thus, we aimed to investigate the events resulting from RIN-5F cells exposure to nanomolar concentrations of toxic hIAPP aggregates. We found an early and transient rise of NADPH oxidase activity resulting from increased Nox1 expression following the engagement of receptor for advanced glycation end-products (RAGE) by hIAPP aggregates. Unexpectedly, NADPH oxidase activation was not accompanied by a significant ROS increase and the lipoperoxidation level was significantly reduced. Indeed, cell exposure to hIAPP aggregates affected the antioxidant defences, inducing a significant increase of the expression and activity of catalase and glutathione peroxidase. We conclude that exposure of pancreatic β-cells to nanomolar concentrations of hIAPP aggregates for a short time induces an hormetic response via the RAGE-Nox1 axis; the latter stimulates the enzymatic antioxidant defences that preserve the cells against oxidative stress damage

Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure

Mitochondrial (mt) DNA depletion and oxidative mtDNA damage have been implicated in the process of pathological cardiac remodeling. Whether these features are present in the early phase of maladaptive cardiac remodeling, that is, during compensated cardiac hypertrophy, is still unknown. We compared the morphologic and molecular features of mt biogenesis and markers of oxidative stress in human heart from adult subjects with compensated hypertrophic cardiomyopathy and heart failure. We have shown that mtDNA depletion is a constant feature of both conditions. A quantitative loss of mtDNA content was associated with significant down-regulation of selected modulators of mt biogenesis and decreased expression of proteins involved in mtDNA maintenance. Interestingly, mtDNA depletion characterized also the end-stage phase of cardiomyopathies due to a primary mtDNA defect. Oxidative stress damage was detected only in failing myocardium

Antagonism/Agonism modulation to build novel antihypertensives selectively triggering i1-imidazoline receptor activation

Pharmacological studies have suggested that I1-imidazoline receptors are involved in the regulation of cardiovascular function and that selective I1-agonists, devoid of the side effects associated with the common hypotensive α2-adrenoreceptor agonists, might be considered as a second generation of centrally acting antihypertensives. Therefore, in the present study, inspired by the antihypertensive behavior of our selective I1-agonist 4, we designed, prepared, and studied the novel analogues 5-9. A selective I1-profile, associated with significant hemodinamic effects, was displayed by 5, 8, and 9. Interestingly, the highest potency and longest lasting activity displayed by 8 (carbomethyline) suggested that van der Waals interactions, promoted by the ortho methyl decoration of its aromatic moiety, are particularly advantageous. In addition, in analogy to what was noted for (S)-(+)-4, the observation that only (S)-(+)-8 displayed significant hemodynamic effects unequivocally confirmed the stereospecific nature of the I1 proteins

A Contract Law for the Age of Digital Platforms? An introduction

The essays which make up this book are the results of a joint effort. Its origin can be traced back to the beginning of 2020, when among the anxieties raised by a mysterious new virus, a group of PhD researchers and scholars of the University of Pisa informally coalesced, as it were, around the elusive notion of ‘platform’ and the peculiarly asymmetric nature of the platform-user relationship. Indeed, both sectoral legislation and transversal regulatory regimes somehow assume that these transactions should be regarded as asymmetric contracts. In view of the power of the platform to shape both the terms of the relationship and the infrastructure in which it takes place, however, it seemed open to discussion whether the asymmetry between the parties could adequately be tackled by extant contract law instruments. Exploring the potential and limits of a contract law for the age of digital platforms seemed thus a topical challenge for future scholarship. The idea of a PhD seminar took shape in a few (digital, ça va sans dire) meetings over the bleak and secluded days of the springtime 2020, in the form of a dialogue between PhD researchers and young legal scholar, chosen amongst the brightest in the field

Ragioni del diritto e ragionamenti nel diritto

Atti del convegno del 29 maggio 2019, dedicato al libro di Umberto Breccia "Le ragioni del Diritto" (Pacini, 2019

Monoamine Oxidase Is Overactivated in Left and Right Ventricles from Ischemic Hearts: An Intriguing Therapeutic Target

Growing evidence indicates that reactive oxygen species (ROS) may play a key role in human heart failure (HF). Monoamine oxidase (MAO) is emerging as a major ROS source in several cardiomyopathies. However, little is known about MAO activity in human failing heart and its relationship with redox imbalance. Therefore, we measured MAO activity in the left (LV) and in the right (RV) ventricle of human nonfailing (NF) and in end-stage ischemic (IHD) and nonischemic failing hearts. We found that both MAO isoforms (MAO-A/B) significantly increased in terms of activity and expression levels only in IHD ventricles. Catalase and aldehyde dehydrogenase-2 activities (ALDH-2), both implicated in MAO-catalyzed catecholamine catabolism, were significantly elevated in the failing LV, whereas, in the RV, statistical significance was observed only for ALDH-2. Oxidative stress markers levels were significantly increased only in the failing RV. Actin oxidation was significantly elevated in both failing ventricles and related to MAO-A activity and to functional parameters. These data suggest a close association between MAO-A-dependent ROS generation, actin oxidation, and ventricular dysfunction. This latter finding points to a possible pathogenic role of MAO-A in human myocardial failure supporting the idea that MAO-A could be a new therapeutic target in HF

Enhanced ROS production by NADPH oxidase is correlated to changes in antioxidant enzyme activity in human heart failure

In pathological conditions, the balance between reactive oxygen species (ROS) and antioxidants may shift toward a relative increase of ROS, resulting in oxidative stress. Conflicting data are available on antioxidant defenses in human failing heart and they are limited to the left ventricle. Thus, we aimed to investigate and compare the source of oxidant and antioxidant enzyme activities in the right (RV) and left (LV) ventricles of human failing hearts. We found a significant increase in superoxide production only by NADPH oxidase in both failing ventricles, more marked in RV. Despite unchanged mRNA or protein expression, catalase (CAT) and glutathione peroxidase (GPx) activities were increased, and their increases reflected the levels of Tyr phosphorylation of the respective enzyme. Manganese superoxide dismutase (Mn-SOD) activity appeared unchanged. The increase in NADPH oxidase-dependent superoxide production positively correlated with the activation of both CAT and GPx. However, the slope of the linear correlation (m) was steeper in LV than in RV for GPx (LV: m = 2.416; RV: m = 1.485) and CAT (LV: m = 1.007; RV: m = 0.354). Accordingly, malondialdehyde levels, an indirect index of oxidative stress, were significantly higher in the RV than LV. We conclude that in human failing RV and LV, oxidative stress is associated with activation of antioxidant enzyme activity. This activation is likely due to post-translational modifications and more evident in LV. Overall, these findings suggest a reduced protection of RV against oxidative stress and its potential contribution to the progression toward overt heart failure. (C) 2009 Elsevier B.V. All rights reserved

Antagonism/Agonism Modulation to Build Novel Antihypertensives Selectively Triggering I₁‑Imidazoline Receptor Activation

Pharmacological studies have suggested that I₁-imidazoline receptors are involved in the regulation of cardiovascular function and that selective I₁-agonists, devoid of the side effects associated with the common hypotensive α₂-adrenoreceptor agonists, might be considered as a second generation of centrally acting antihypertensives. Therefore, in the present study, inspired by the antihypertensive behavior of our selective I₁-agonist <b>4</b>, we designed, prepared, and studied the novel analogues <b>5</b>–<b>9</b>. A selective I₁-profile, associated with significant hemodinamic effects, was displayed by <b>5</b>, <b>8</b>, and <b>9</b>. Interestingly, the highest potency and longest lasting activity displayed by <b>8</b> (carbomethyline) suggested that van der Waals interactions, promoted by the ortho methyl decoration of its aromatic moiety, are particularly advantageous. In addition, in analogy to what was noted for (<i>S</i>)-(+)-<b>4</b>, the observation that only (<i>S</i>)-(+)-<b>8</b> displayed significant hemodynamic effects unequivocally confirmed the stereospecific nature of the I₁ proteins