1,721,025 research outputs found
Osteoprotegerin: a pancreatic islets dysfunction and vascular injury modulator
No full textBackground. Osteoprotegerin (OPG) is a soluble glycoprotein of the tumor necrosis factor (TNF) receptor superfamily, which was initially identified as a key regulator in bone turnover. It acts as a decoy receptor for the receptor activator of nuclear factor kB ligand (RANKL) and for the TNF-related apoptosis-inducing ligand (TRAIL), counterbalancing their biological effects. OPG is produced by a wide range of tissues, including the cardiovascular system, and its levels are particularly high in aortic and renal arteries. Several studies have clearly demonstrated that the serum levels of OPG are elevated in diabetic and nondiabetic patients affected by cardiovascular diseases, and increased levels of OPG represent a risk factor for cardiovascular mortality, especially in diabetic patients. However, in spite of the reported findings, the physiopathological role of elevated serum levels of OPG in vascular biology and in pancreatic islet function are not well understood.
Aim of the study. The aims of our studies were:
Study 1. Evaluate the potential role of OPG in the pathogenesis of diabetes associated atherosclerosis.
Study 2. Investigate OPG effects on pancreatic islet function and its interaction with local pancreatic renin-angiotensin system (RAS).
Materials and Methods. Study 1.A. In vivo study: 80 apoE knockout male mice were further randomized into 4 groups (n=20) and followed for 3 months. One group of non diabetic animals received an intraperitoneal (i.p.) injection of vehicle and served as a control; another group of non-diabetic animals received every 3 weeks an i.p. injection of human recombinant OPG (OPG). The other two groups, rendered diabetic by 5 daily i.p. injections of streptozotocin (55mg/Kg/die), received injections of OPG or an equivalent volume of vehicle. At the end of the study, animals were culled, the blood was collected for biochemical analysis, and the entire aorta was excised out to study the total plaques extent and to evaluate the lesion composition and complexity of the aortic plaques. B. In vitro study: Murine vascular smooth muscle cells (VMSC) were treated with different concentrations of OPG, TGFβ and SB431542 (TGFβ- type 1 receptor inhibitor). Subsequently, cellular proliferation and pro-fibrotic markers gene expression were evaluated at different time points. OPG protein release was measured in growth media (ELISA technique).
Study 2. 40 male mice C57Bl/6J, aged 10 weeks, were randomized into 4 groups (n=10) and studied for 3 months. Group 1 received every 3 weeks an i.p. injection of vehicle and served
as a control. Group 2 received every 3 weeks an i.p. injection of OPG. Group 3 received the ACE inhibitor ramipril at the dose of 10mg/Kg/die in drinking water in co-treatment with i.p. injections of vehicle. Group 4 received ramipril in co-treatment with i.p. injections of OPG. At the end of the study, animals were culled, the blood was collected for biochemical analysis, and the pancreas was dissected out for subsequent quantitative RT-PCR measurements and immunohistochemical analysis.
Results. Study 1.A. At the end of the study, diabetic animals injected with OPG presented a significant increase in total plaques extent, with an increase of smooth muscle cells content in aortic plaques. Moreover OPG treated animals showed an increase in the collagen content in aortic media in respect to control mice. B. OPG promoted VSMC proliferation and pro-fibrotic markers gene expression. TGFβ treatment of VSMC induced a dose-dependent increase of OPG gene and protein expression, that was completed prevented by pre-treatment with the SB431542 inhibitor.
Study 2. OPG-treated animals showed increased islet monocyte-macrophage infiltration, fibrosis and apoptosis with reduction of islet function. The remodeling of islet architecture was associated with increased pancreatic expression of components of the RAS, growth factor genes (TGFβ and CTGF) and inflammatory molecules (MCP-1 and VCAM-1). Prevention of these changes with improvement of insulin secretion was observed in ramipril treated animals.
Conclusion. Study 1.A-B OPG seems to play an important pathogenetic role in the development and progression of diabetic atherosclerosis.
Study 2. Our data suggest that OPG might play an important role in promoting beta cell dysfunction and the upregulation of the local RAS represents one possible mechanism responsible for the OPG-induced beta cell dysfunction
Gas emission centres on Mars surface and putative biological contribution: insights on hydrothermal fluid circulation in the upper crust
Full text linkThe herein presented work aims to develop and expand Mars geological exploration in a search for life prospective and, accordingly, water resurgence features and possible degassing centers have been given a central role in the target selection and process investigation. Hydrothermal fluid circulation in the Martian crust is among the natural processes characterized by the combined involvement of fluids such water and methane so defining a potential set of environments prone to biosphere growth and flourish. Subsurface fluid flow is a key area of planetary science research because fluids affect almost every physical, chemical, mechanical and thermal property of the upper crust. Hydrothermal systems are closely bond to the transport of mass, heat, nutrients and chemical species in hydrogeological systems making these mechanisms central in fields such as volcano-tectonic, deep-biosphere and water/ice cycle.
To step forward toward a new generation of planetary exploration that aims, not only to analyse and map the surfaces of planetary bodies other than Earth, but also to push the survey down in depth, in the first chapter we successfully test the efficiency of a rising technique that allows to probe the subsurface starting from surface case studies: fractal analysis. This method was firstly applied on many different study cases on Earth to investigate the location at depth of magma chambers and sediment source layers beneath volcanic vent and mud volcano fields. We thus took this technique and applied it to many different well-known morphologically convergent features on Mars, but with very different inferred formation process, in order to test if fractal analysis were an efficient methodology to identify spatial patterns linked to system of percolating connected fractures and drained material source depth by outputting the expected outcomes for the different cases. Thanks to the successfully obtained results we fostered the implementation of such method in the planetary exploration research field.
In the second chapter is reported the produced work concerning the exploration and investigation aimed to identify new regions on Mars with a high astrobiological potential through the usage of classic and fractal analyses. Since the main objective of the herein presented work is to spot emission centers linked to water and methane release, we set our starting point on the search for fields of pitted mounds, which are good candidate morphologies for our purposes. Many different areas, with large coverages and very different geological context showed a relationship with systems of connected fractures extending many kilometres beneath the surface. We were not just able to profitably analyse different areas and locate several interesting vast regions, but we observed a systematic linkage between large fields of pitted mounds on the surface and the shallowest interface between gas hydrate-rich cryosphere and hydrosphere hypothesised for the Martian subsurface, so discovering the potential key role of clathrates on a, geologically speaking, recent Mars.
The intriguing results produced and displayed in the first two chapters of this work led to a spectrum of unsolved questions concerning the processes that could be involved in such kind of phenomena. We thus choose to approach this topic from the structural side aiming to produce structural asset interpretations based on fluid circulation evidence, where information is available. In the third chapter, we hence face a propaedeutic explorative study which has the objective to compare sulfate vein networks on several locations on Earth with sulfate veins outcropping in the Gale crater (Curiosity Rover landing site, Mars), that represent the only case of close up acquisitions of Martian features that surely experienced fluid circulation. A better understanding of the structural asset on portions of the Martian surface will progressively lead to a contextualisation of the forces that could have contributed to drive the fluid flows in the upper Martian crust and again pushing the exploration toward the subsurface realm and to the identification of outgassing and water related environments.
In the fourth chapter are exposed preliminary works that further pursue the aim of identify and investigate environments that experienced fluid circulation, backbone of this thesis. On one side, we moved on in exploring the Martian surface throughout the observation of the freshly acquired four-colours images of the CaSSIS camera we are involved in, with remarkable outcomes thanks to the location of light-toned ridges possibly linked to hydrothermal fluid percolation and connected rocks alteration. Contextually, we also approached the question from the compositional side by enhancing spectral libraries with the production of spectral signatures, on ultraviolet- far infrared wavelength span, of minerals belonging to environments that, on Earth, are linked to low temperature hydrothermal circulation and of rare bio-mineralisation features that are siliceous stromatolites.Il lavoro presentato ha lo scopo di sviluppare ed espandere l'esplorazione geologica di Marte nell’ottica di ricerca di ambienti adatti allo sviluppo della vita e, di conseguenza, centri di risalita di acqua e centri di degassamento hanno avuto un ruolo centrale nella selezione degli obiettivi di indagine. La circolazione idrotermale nella crosta marziana è tra i processi naturali caratterizzati dal coinvolgimento combinato di fluidi quali acqua e metano, definendo così un potenziale insieme di ambienti inclini alla crescita e allo sviluppo della biosfera. La circolazione di fluidi nel sottosuolo è un'area chiave nel contesto delle scienze planetarie perché essi influenzano quasi ogni proprietà fisica, chimica, meccanica e termica della crosta superiore. I sistemi idrotermali sono strettamente legati al trasporto di massa, calore, sostanze nutritive e specie chimiche nei sistemi idrogeologici, rendendo questi meccanismi centrali in campi quali il ciclo vulcano-tettonico, la biosfera profonda e il ciclo acqua / ghiaccio.
Per sviluppare una nuova generazione di esplorazione planetaria che mira non solo ad analizzare e mappare le superfici dei corpi planetari diversi dalla Terra, ma anche a sondarne le profondità, nel primo capitolo testiamo con successo l'efficienza di una nuova tecnica che permette di investigare il sottosuolo partendo dalle osservazioni di superficie: l’analisi frattale. Questo metodo è stato applicato per la prima volta sulla Terra per indagare la profondità delle camere magmatiche e degli strati sorgente che alimentano vulcanesimo magmatico e vulcani di fango. Abbiamo quindi applicato questa tecnica a diverse strutture di superficie su Marte con caratteristiche morfologicamente convergenti, ma con processi di formazione molto diversi, al fine di verificare se l'analisi frattale fosse una metodologia efficiente per identificare la presenza di un sistema percolante di fratture connesse e la profondità della sorgente del materiale drenato. I risultati sono stati positivi promuovendone così l'implementazione nel processo di esplorazione planetaria.
Nel secondo capitolo viene riportato il lavoro prodotto relativo all'esplorazione volto a identificare nuove regioni ad alto potenziale su Marte attraverso l'uso di analisi classiche e frattali. Poiché l'obiettivo principale del presente lavoro presentato è quello di individuare i centri di emissione legati al rilascio di acqua e metano, poniamo il nostro punto di partenza nella ricerca di campi di pitted mounds, che sono ottimi candidati per i nostri scopi. Varie aree, con grandi coperture e un contesto geologico molto diverso, hanno mostrato una relazione con sistemi di fratture connesse con estensioni fino svariati chilometri di profondità. Non solo siamo stati in grado di analizzare proficuamente aree diverse e localizzare vaste regioni ad alto interesse, ma abbiamo osservato un collegamento sistematico tra grandi campi di pitted mounds sulla superficie e l'interfaccia più superficiale tra la criosfera ricca in clatrati e l'idrosfera ipotizzata per il sottosuolo marziano, scoprendo così il ruolo chiave che i clatrati potrebbero aver avuto su Marte i un passato geologicamente recente.
I risultati promettenti prodotti e mostrati nei primi due capitoli di questo lavoro hanno portato a uno spettro di domande riguardanti i processi che potrebbero essere coinvolti in questo tipo di fenomeni. Scegliamo quindi di affrontare questo argomento tramite l’interpretazione dell’assetto strutturale basato su evidenze di circolazione di fluidi, in aree in cui tali informazioni sono disponibili. Nel terzo capitolo, quindi, affrontiamo uno studio esplorativo propedeutico che ha l'obiettivo di confrontare sistemi di vene a solfati in diverse località sulla Terra con le vene a solfati affioranti nel Gale crater, che rappresentano l'unico caso di acquisizioni ravvicinate di strutture marziane che sicuramente hanno sperimentato circolazione di fluidi. Una migliore comprensione dell’assetto strutturale su porzioni della superficie marziana può portare progressivamente ad una contestualizzazione delle forze che potrebbero aver contribuito a guidare i flussi di fluido nella crosta superiore marziana e inoltre a migliorare la corrente conoscenza del sottosuolo marziano nonché all’identificazione di ambienti legati all'acqua.
Nel quarto capitolo sono esposti i lavori preliminari che hanno come obiettivo quello di identificare e indagare ambienti che hanno subito la circolazione di fluidi, spina dorsale di questa tesi. Da un lato, siamo andati avanti nell'esplorazione della superficie marziana attraverso l'osservazione delle immagini a quattro colori appena acquisite della camera CaSSIS, con esiti notevoli grazie all’individuazione di creste probabilmente legate alla percolazione di fluido idrotermale e all'alterazione delle rocce incassanti. Contestualmente, abbiamo anche affrontato la questione dal lato composizionale migliorando le librerie spettrali con la produzione di firme spettrali, in lunghezze d'onda dall'ultravioletto al lontano infrarosso, di minerali appartenenti ad ambienti che, sulla Terra, sono legati alla circolazione idrotermale a bassa temperatura e di rare bio-mineralizzazioni quali le stromatoliti silicee
Potential role of TRAIL in the management of autoimmune diabetes mellitus
No full textType 1 diabetes mellitus (T1DM) is an autoimmune disease, due to the immune-mediated destruction of pancreatic β-cells, whose incidence has been steadily increasing during the last decades. Insulin replacement therapy can treat T1DM, which, however, is still associated with substantial morbidity and mortality. For this reason, great effort is being put into developing strategies that could eventually prevent and/or cure this disease. These strategies are mainly focused on blocking the immune system from attacking β-cells together with functional islet restoration either by regeneration or transplantation. Recent experimental evidences suggest that TNFrelated apoptosis-inducing ligand (TRAIL), which is an immune system modulator protein, could represent an interesting candidate for the cure for T1DM and/or its complications. Here we review the evidences on the potential role of TRAIL in the management of T1DM
Roles and Clinical Applications of OPG and TRAIL as Biomarkers in Cardiovascular Disease
Full text linkCardiovascular diseases (CVD) remain the major cause of death and premature disability in Western societies. Assessing the risk of CVD is an important aspect in clinical decision-making. Among the growing number of molecules that are studied for their potential utility as CVD biomarkers, a lot of attention has been focused on osteoprotegerin (OPG) and its ligands, which are receptor activator of nuclear factor κB ligand (RANKL) and TNF-related apoptosis-inducing ligand. Based on the existing literature and on our experience in this field, here we review what the possible roles of OPG and TRAIL in CVD are and their potential utility as CVD biomarkers
Prevention of accelerated atherosclerosis by AT1 receptor blockade in experimental renal failure.
No full textThe mechanisms of uraemia-induced atherosclerosis have not been fully delineated. The aims of this study were (i) to investigate the extent and the phenotype of atherosclerosis, including the activation of local renin-angiotensin system (RAS), in a mouse model of mild uraemia and (ii) to determine the effects of angiotensin II type1 (AT1) receptor blockade on the uraemic atherosclerosis, clarifying the mechanisms of its action.Mild uraemia was induced by 5/6 nephrectomy in 8-week-old apo E-deficient mice (apoE-KO). After nephrectomy, the animals received either treatment with candesartan or no treatment for 12-weeks. Sham-operated apoE-KO mice were used as controls.Uraemia led to a two-fold increase in aortic plaque area. This was associated with a significant upregulation of aortic angiotensin-converting enzyme (ACE), AT1 receptor, connective tissue growth factor (CTGF), monocyte chemoattractant protein (MCP)-1 and vascular cell adhesion molecule (VCAM)-1. Candesartan significantly reduced aortic atherosclerosis, prevented the upregulation of the uraemia-induced genes and led to changes predicting greater stability of the plaques, without influencing blood pressure or serum lipids.This study indicates that uraemia leads to an acceleration of aortic atherosclerosis. The upregulation of aortic RAS and the reduced atherosclerosis following AT1 receptor blocker treatment highlights the pivotal role of the local RAS in the development and acceleration of atherosclerosis in uraemia
Dyslipidemia and Diabetes Increase the OPG/TRAIL Ratio in the Cardiovascular System
Full text linkBackground. Dyslipidemia and diabetes are two of the most well established risk factors for the development of cardiovascular disease (CVD). Both of them usually activate a complex range of pathogenic pathways leading to organ damage. Here we hypothesized that dyslipidemia and diabetes could affect osteoprotegerin (OPG) and TNF-related apoptosis-inducing ligand (TRAIL) expression in the vessels and the heart. Materials and Methods. Gene and protein expression of OPG, TRAIL, and OPG/TRAIL ratio were quantified in the aorta and the hearts of control mice, dyslipidemic mice, and diabetic mice. Results. Diabetes significantly increased OPG and the OPG/TRAIL ratio expression in the aorta, while dyslipidemia was the major determinant of the changes observed in the heart, where it significantly increased OPG and reduced TRAIL expression, thus increasing cardiac OPG/TRAIL ratio. Conclusions. This work shows that both dyslipidemia and diabetes affect OPG/TRAIL ratio in the cardiovascular system. This could contribute to the changes in circulating OPG/TRAIL which are observed in patients with diabetes and CVD. Most importantly, these changes could mediate/contribute to atherosclerosis development and cardiac remodeling
Orally administered microencapsulated lysozyme downregulates serum AGE and reduces the severity of early-stage diabetic nephropathy
No full textDiabetic nephropathy is the leading cause of end-stage kidney disease in developed countries and is related to chronic hyperglycaemia. The increased production and tissue deposition of advanced glycation end products (AGE) are known to play a major role in the pathogenesis of diabetic kidney damage. This study was undertaken to determine if lysozyme (LZ), microencapsulated in orally administrable chitosan-coated alginate microspheres (MS), is effective against the early changes seen in the initial stages of diabetic nephropathy.
Methods
LZ-containing MS (MSLZ) and an equivalent dose (equidose) of nonencapsulated LZ were given as oral treatments. LZ was administered to Wistar rats for seven weeks after diabetes induction with streptozotocin.
Results
The results showed that microencapsulated LZ treatment significantly reduced the concentration of serum AGE in the circulation and their deposition in the kidneys. Likewise, MSLZ significantly prevented the development of microalbuminuria compared with untreated diabetic rats. Furthermore, MSLZ significantly prevented the development of glomerular and renal hypertrophy as well as overexpression of AGE receptors (RAGE). An equidose of free LZ had little or no effect whatsoever.
Conclusion
Our study supports a relationship between serum AGE and nephropathy in diabetes, and suggests that orally administered microencapsulated LZ can exert kidney-protective activity in a diabetic animal model
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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