Inflamació com a nexe d'unió entre obesitat i complicacions metabòliques: esteatosi hepàtica

La inflamació s’ha considerat tradicionalment com un mecanisme de defensa, molt lligat a la supervivència de l’espècie, per la seva capacitat de combatre les infeccions o restaurar el dany produït. No obstant, un estat d’inflamació crònic produeix un efecte totalment contrari, que s’associa a un mal funcionament de teixits i òrgans. L’objectiu d’aquest treball és l’estudi de la proteïna quimioatraient de monòcits-1 (MCP-1), una proteïna descrita per la seva funció en l’atracció de monòcits a la lesió arterioscleròtica, i que pot tenir un paper rellevant en el metabolisme. Els resultats mostren que MCP-1 està implicada en el control del metabolisme dels lípids i de la glucosa, i que l’expressió hepàtica de MCP-1 està sobre-expressada per la dieta i que contribueix al desenvolupament i progressió de l’esteatosi hepàtica en el model LDLr-/-. Precisament, l’últim treball demostra que l’estudi dels canvis metabolòmics en el teixit hepàtic ens pot ajudar a entendre aquesta patologiaInflammation has been traditionally regarded as a defense mechanism, closely linked to the survival of the species for their ability to fight infections or restore the damage. However, a state of chronic inflammation produced a completely opposite effect, which is associated with tissue and organ malfunction. The aim of this work is the study of monocyte chemoattractant protein-1 (MCP-1), a protein described by its role in attracting monocytes to atherosclerotic lesions, which may also play an important role in metabolism. The results show that MCP-1 is involved in the control of lipids and glucose metabolism. Hepatic MCP-1 is over-expressed by diet and contributes to the development and progression of fatty liver disease (NASH) in LDLr-/- model. Indeed, the latest study shows that metabolomic changes in the liver can help us to understand the NASH progression

Insulin Resistance, Inflammation, and Obesity: Role of Monocyte Chemoattractant Protein-1 (or CCL2) in the Regulation of Metabolism

To maintain homeostasis under diverse metabolic conditions, it is necessary to coordinate nutrient-sensing pathways with the immune response. This coordination requires a complex relationship between cells, hormones, and cytokines in which inflammatory and metabolic pathways are convergent at multiple levels. Recruitment of macrophages to metabolically compromised tissue is a primary event in which chemokines play a crucial role. However, chemokines may also transmit cell signals that generate multiple responses, most unrelated to chemotaxis, that are involved in different biological processes. We have reviewed the evidence showing that monocyte chemoattractant protein-1 (MCP-1 or CCL2) may have a systemic role in the regulation of metabolism that sometimes is not necessarily linked to the traffic of inflammatory cells to susceptible tissues. Main topics cover the relationship between MCP-1/CCL2, insulin resistance, inflammation, obesity, and related metabolic disturbances

AuRUS: explaining the validation of UML/OCL conceptual schemas

The validation and the verification of conceptual schemas have attracted a lot of interest during the last years, and several tools have been developed to automate this process as much as possible. This is achieved, in general, by assessing whether the schema satisfies different kinds of desirable properties which ensure that the schema is correct. In this paper we describe AuRUS, a tool we have developed to analyze UML/OCL conceptual schemas and to explain their (in)correctness. When a property is satisfied, AuRUS provides a sample instantiation of the schema showing a particular situation where the property holds. When it is not, AuRUS provides an explanation for such unsatisfiability, i.e., a set of integrity constraints which is in contradiction with the property.Peer ReviewedPostprint (author’s final draft

Methodological constraints in interpreting serum paraoxonase-1 activity measurements: an example from a study in HIV-infected patients

<p>Abstract</p> <p>Background</p> <p>Paraoxonase-1 (PON1) is an antioxidant enzyme that attenuates the production of the monocyte chemoattractant protein-1 (MCP-1) <it>in vitro</it>. Although oxidation and inflammation are closely related processes, the association between PON1 and MCP-1 has not been completely characterised due, probably, to that the current use of synthetic substrates for PON1 measurement limits the interpretation of the data. In the present study, we explored the relationships between the circulating levels of PON1 and MCP-1 in human immunodeficiency virus-infected patients in relation to the multifunctional capabilities of PON1.</p> <p>Methods</p> <p>We measured selected variables in 227 patients and in a control group of 409 participants. Serum PON1 esterase and lactonase activities were measured as the rates of hydrolysis of paraoxon and of 5-(thiobutyl)-butyrolactone, respectively. Oxidised LDL and MCP-1 concentrations were determined by enzyme-linked immunosorbent assay. High-density lipoproteins cholesterol, apolipoprotein A-I, and C-reactive protein concentrations were measured by standard automated methods.</p> <p>Results</p> <p>There were significant relationships between PON1 activity and several indices of oxidation and inflammation in control subjects and in infected patients. However, these relationships varied not only with disease status but also on the type of substrate used for PON1 measurement.</p> <p>Conclusion</p> <p>The present study is a cautionary tale highlighting that results of clinical studies on PON1 may vary depending on the methods used as well as the disease studied. Until more specific methods using physiologically-akin substrates are developed for PON1 measurement, we suggest the simultaneous employment of at least two different substrates in order to improve the reliability of the results obtained.</p

Immunometabolism is a key factor for the persistent spontaneous elite control of HIV-1 infection

Approximately 25% of elite controllers (ECs) lose their virological control by mechanisms that are only partially known. Recently, immunovirological and proteomic factors have been associated to the loss of spontaneous control. Our aim was to perform a metabolomic approach to identify the underlying mechanistic pathways and potential biomarkers associated with this loss of control. Methods: Plasma samples from EC who spontaneously lost virological control (Transient Controllers, TC, n=8), at two and one year before the loss of control, were comparedwith a control group of ECwho persistently maintained virological control during the same follow-up period (Persistent Controllers, PC, n=8). The determination of metabolites and plasma lipids was performed by GC-qTOF and LC-qTOF using targeted and untargeted approaches. Metabolite levels were associated with the polyfunctionality of HIV-specific CD8+T-cell response. Findings: Our data suggest that, before the loss of control, TCs showed a specific circulating metabolomic profile characterized by aerobic glycolytic metabolism, deregulated mitochondrial function, oxidative stress and increased immunological activation. In addition, CD8+ T-cell polyfunctionality was strongly associated with metabolite levels. Finally, valine was the main differentiating factor between TCs and PCs. Interpretation: All these metabolomic differences should be considered not only as potential biomarkers but also as therapeutic targets in HIV infection.Instituto Carlos III PI10/02635 PI13/00796 PI16/00503 PI12/02283 PI16/00684 CPII014/00025 FI14/00431 FI17/00186 INT11/240 INT12/282 INT15/226Fondos Europeos para el Desarrollo Regional PI10/02635 PI13/00796 PI16/00503 PI12/02283 PI16/00684 CPII014/00025 FI14/00431 FI17/00186FEDER PI10/02635 PI13/00796 PI16/00503 PI12/02283 PI16/00684 CPII014/00025 FI14/00431 FI17/00186FEDER PI10/02635 PI13/00796 PI16/00503 PI12/02283 PI16/00684 CPII014/00025 FI14/00431 FI17/00186Programa de Suport als Grups de Recerca 2017SGR948 2014SGR250Gilead Fellowship Program GLD14/293 GLD17/00299Red de Investigación en Sida RD12/0017/0005 RD16/0025/0006 RD12/0017/0029 RD16/0025/0020Junta de Andalucía C-0032/17Generalitat de Catalunya PERIS SLT002/16/0010

PPARs in Regulation of Paraoxonases: Control of Oxidative Stress and Inflammation Pathways

The paraoxonase (PON) group of enzymes, composed of PON1, PON2, and PON3, play an important role in decreasing oxidative stress by degrading lipid peroxides. PON1 synthesis is upregulated by PPAR. Several pharmacological compounds (acting as antioxidants and, hence, atheroprotective) stimulate both PPAR activity and PON1 expression. Recent evidence suggests that PON1 and the monocyte chemoattractant protein-1 (MCP-1) are involved in coordinating the inflammatory response in damaged tissues; PPAR may be central in the regulation of these biochemical pathways. This article reviews the state of knowledge on PON1 biochemistry and function, the influence of genetic variation, and the regulation of PON1 expression by pharmaceutical compounds that increase PPAR activity. We also describe recent lines of evidence suggesting links between PON1 and MCP-1 and how their production may be regulated by PPAR

Decreased paraoxonase-1 activity is associated with alterations of high-density lipoprotein particles in chronic liver impairment

<p>Abstract</p> <p>Background</p> <p>Paraoxonase-1 (PON1), a lactonase synthesized by the liver, circulates in blood bound to high-density lipoproteins (HDL). This enzyme is thought to degrade oxidized phospholipids and play an important role in the organism's antioxidant and anti-inflammatory system. Chronic liver diseases are characterized by decreased serum PON1 activity. The aim of the present study was to investigate the compositional changes in HDL that could influence PON1 activity in liver impairment.</p> <p>Methods</p> <p>The study was performed in samples from five patients with advanced liver cirrhosis and with preserved renal function, chosen on the basis of having low serum PON1 activity and high serum PON1 concentration. As a control group, we accessed five healthy volunteers from among our hospital staff. Lipid and protein compositional analysis of lipoprotein particles were done by high-performance liquid chromatography, gel electrophoresis, and Western-Blot.</p> <p>Results</p> <p>HDL particles from cirrhotic patients had an increased phospholipid content that was inversely correlated to PON1 activity. The HDL particles contained high levels of PON1 that corresponded, in part, to an immunoreactive protein of high molecular weight (55 kDa) not present in control subjects. This protein was identified as glycosylated PON1 and was also present in biopsies from patients with steatosis and from rats with CCl₄-induced hepatic impairment. These changes were associated with an increased plasma concentration of markers of oxidative stress, inflammation and fibrogenesis.</p> <p>Conclusion</p> <p>Abnormalities in the composition of lipids and proteins of HDL particles, including PON1 glycosylation, are associated with the decrease in serum PON1 activity in patients with liver disease. These alterations may adversely affect the protective role of HDL against oxidative stress and inflammation in these patients.</p

Multi-omics in HIV: searching insights to understand immunological non-response in PLHIV

Antiretroviral therapy (ART) induces persistent suppression of HIV-1 replication and gradual recovery of T-cell counts, and consequently, morbidity and mortality from HIV-related illnesses have been significantly reduced. However, in approximately 30% of people living with HIV (PLHIV) on ART, CD4+ T-cell counts fail to normalize despite ART and complete suppression of HIV viral load, resulting in severe immune dysfunction, which may represent an increased risk of clinical progression to AIDS and non-AIDS events as well as increased mortality. These patients are referred to as “immune inadequate responders”, “immunodiscordant responders” or “immune nonresponders (INR)”. The molecular mechanisms underlying poor CD4+ T-cell recovery are still unclear. In this sense, the use of omics sciences has shed light on possible factors involved in the activity and metabolic dysregulation of immune cells during the failure of CD4+ T-cell recovery in INR. Moreover, identification of key molecules by omics approaches allows for the proposal of potential biomarkers or therapeutic targets to improve CD4+ T-cell recovery and the quality of life of these patients. Hence, this review aimed to summarize the information obtained through different omics concerning the molecular factors and pathways associated with the INR phenotype to better understand the complexity of this immunological status in HIV infection

Evolution of Serum Acute-Phase Glycoproteins Assessed by 1H-NMR in HIV Elite Controllers

Elite controllers (ECs) are an exceptional group of people living with HIV (PLWH) who maintain undetectable viral loads (VLs) despite not being on antiretroviral therapy (ART). However, this phenotype is heterogeneous, with some of these subjects losing virological control over time. In this longitudinal retrospective study, serum acute-phase glycoprotein profile assessed by proton nuclear magnetic resonance (1H-NMR) was determined in 11 transient controllers (TCs) who spontaneously lost virological control and 11 persistent controllers (PCs) who persistently maintained virological control over time. Both PCs and TCs showed similar acute-phase glycoprotein profiles, even when TCs lost the virological control (GlycB, p = 0.824 and GlycA, p = 0.710), and the serum acute-phase glycoprotein signature in PCs did not differ from that in HIV-negative subjects (GlycB, p = 0.151 and GlycA, p = 0.243). Differences in serum glycoproteins A and B were significant only in ECs compared to HIV-typical progressors (TPs) with < 100 CD4+ T-cells (p < 0.001). 1H-NMR acute-phase glycoprotein profile does not distinguish TCs form PCs before the loss of viral control. ECs maintain a low-grade inflammatory state compared to TPs. PCs revealed a closer serum signature to HIV-negative subjects, reaffirming this phenotype as a closer model of functional control of HIV.This research was funded by the Fondo de Investigacion Sanitaria [PI16/00503, PI19/01337 and PI20/00326]-ISCIII-FEDER (co-funded by the European Regional Development Fund/European Social Fund; “A way to make Europe”/“Investing in your future”); Programa de Suport als Grups de Recerca AGAUR (2017SGR948); the SPANISH AIDS Research Network [RD12/0017/0005, RD12/0025/0001, RD16/0025/0006]-ISCIII-FEDER (Spain) and Centro de Investigación Biomédica en Red de Enfermedades Infecciosas-ISCIII [CB21/13/00015, CB21/13/00020, CB13/21/00086], Madrid, Spain. JM is supported by the Universitat Rovira i Virgili under grant agreement “2019PMF-PIPF-18,” through the call “Martí Franquès Research Fellowship Programme”. FV is supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII. AR is supported by a grant from IISPV through the project “2019/IISPV/05” (Boosting Young Talent), by GeSIDA through the “III Premio para Jóvenes Investigadores 2019” and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00146” through the Miguel Servet Program.S