1,721,023 research outputs found
Modulating Autoimmunity against LDL: Development of a Vaccine against Atherosclerosis
Full text linkAtherosclerosis is a chronic inflammatory disease of the arterial wall that leads to the build-up of occluding atherosclerotic plaques. Its clinical sequelae, myocardial infarction and stroke, represent the most frequent causes of death worldwide. Atherosclerosis is a multifactorial pathology that involves traditional risk factors and chronic low-grade inflammation in the atherosclerotic plaque and systemically. This process is accompanied by a strong autoimmune response that involves autoreactive T cells in lymph nodes and atherosclerotic plaques, as well as autoantibodies that recognize low-density lipoprotein (LDL) and its main protein component apolipoprotein B (ApoB). In the past 60 years, numerous preclinical observations have suggested that immunomodulatory vaccination with LDL, ApoB, or its peptides has the potential to specifically dampen autoimmunity, enhance tolerance to atherosclerosis-specific antigens, and protect from experimental atherosclerosis in mouse models. Here, we summarize and discuss mechanisms, challenges, and therapeutic opportunities of immunomodulatory vaccination and other strategies to enhance protective immunity in atherosclerosis.Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Albert Ludwigs University of Freiburg; AlemaniaFil: Abogunloko, Tijani. Albert Ludwigs University of Freiburg; AlemaniaFil: Wolf, Dennis. Albert Ludwigs University of Freiburg; Alemani
Redox and inflammatory mechanisms linking air pollution particulate matter with cardiometabolic derangements
No full textAir pollution is the largest environmental risk factor for disease and premature death. Among the different components that are present in polluted air, fine particulate matter below 2.5 μm in diameter (PM2.5) has been identified as the main hazardous constituent. PM2.5 mainly arises from fossil fuel combustion during power generation, industrial processes, and transportation. Exposure to PM2.5 correlates with enhanced mortality risk from cardiovascular diseases (CVD), such as myocardial infarction and stroke. Over the last decade, it has been increasingly suggested that PM2.5 affects CVD already at the stage of risk factor development. Among the multiple biological mechanisms that have been described, the interplay between oxidative stress and inflammation has been consistently highlighted as one of the main drivers of pulmonary, systemic, and cardiovascular effects of PM2.5 exposure. In this context, PM2.5 uptake by tissue-resident immune cells in the lung promotes oxidative and inflammatory mediators release that alter tissue homeostasis at remote locations. This pathway is central for PM2.5 pathogenesis and might account for the accelerated development of risk factors for CVD, including obesity and diabetes. However, transmission and end-organ mechanisms that explain PM2.5-induced impaired function in metabolic active organs are not completely understood. In this review, the main features of PM2.5 physicochemical characteristics related to PM2.5 ability to induce oxidative stress and inflammation will be presented. Hallmark and recent epidemiological and interventional studies will be summarized and discussed in the context of current air quality guidelines and legislation, knowledge gaps, and inequities. Lastly, mechanistic studies at the intersection between redox metabolism, inflammation, and function will be discussed, with focus on heart and adipose tissue alterations. By offering an integrated analysis of PM2.5-induced effects on cardiometabolic derangements, this review aims to contribute to a better understanding of the pathogenesis and potential interventions of air pollution-related CVD.Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentin
Skin damage mechanisms related to airborne particulate matter exposure
Full text linkEpidemiological studies suggest a correlation between increased airborne particulate matter (PM) and adverse health effects. The mechanisms of PM-health effects are believed to involve oxidative stress and inflammation. To evaluate the ability of PM promoting skin tissue damage, one of the main organs exposed to outdoor pollutants, we analyzed the effect of concentrated ambient particles (CAPs) in a reconstructed human epidermis (RHE) model. RHE tissues were exposed to 25 or 100 μg/ml CAPs for 24 or 48 h. Data showed that RHE seems to be more susceptible to CAPs-induced toxicity after 48 h exposure than after 24 h. We found a local reactive O2 species (ROS) production increase generated from metals present on the particle, which contributes to lipids oxidation. Furthermore, as a consequence of altered redox status, NFkB nucleus translocation was increase upon CAPs exposure, as well as cyclooxygenase 2 and cytochrome P450 levels, which may be involved in the inflammatory response initiated by PM. CAPs also triggered an apoptotic process in skin. Surprisingly, by transition electron microscopy analysis we showed that CAPs were able to penetrate skin tissues. These findings contribute to the understanding of the cutaneous pathophysiological mechanisms initiated by CAPs exposure, where oxidative stress and inflammation may play predominant roles.Fil: Magnani, Natalia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Muresan, Ximena M.. Universita Di Ferrara; ItaliaFil: Belmonte, Giuseppe. Universita Di Ferrara; ItaliaFil: Cervellati, Franco. Universita Di Ferrara; ItaliaFil: Sticozzi, Claudia. Universita Di Ferrara; ItaliaFil: Pecorelli, Alessandra. Universita Di Ferrara; ItaliaFil: Miracco, Clelia. Università Degli Studi Di Siena; ItaliaFil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Evelson, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Valacchi, Giuseppe. Universita Di Ferrara; Itali
Exposición aguda a partículas de contaminación ambiental: función cardíaca, estrés oxidativo y mecanismos de respuesta inflamatoria sistémica
Full text linkThe exposure to environmental particulate matter (PM) is associated with increased cardiovascular morbidity and mortality rates. Oxidative stress and inflammation have been suggested to play a central role. However, the underlying mechanisms are poorly understood. The aim of this work was to evaluate this hypothesis in acute models of exposure to a combustion-derived PM surrogate (ROFA), by different in vivo and in vitro approaches. Heart oxidative and energetic metabolism was altered in ROFA-exposed mice, as well as mitochondrial function and cardiac contractile and diastolic reserve. Increased levels of oxidative stress and inflammation markers were also found in ROFA-exposed mice, together with intravascular polymorphonuclear leukocytes activation. ROFA-induced systemic inflammation promoted leukocyte trafficking, by the activation of endothelial and myeloid cells. Monocyte depletion prevented local and systemic inflammation, while in vivo TNF-? blockage reduced ROFA-induced cardiac alterations. These findings indicate that oxidative stress and inflammation are triggered by the exposure to PM, which might be associated to the observed cardiovascular alterations reported after PM inhalation.Fil: Marchini, Timoteo Oscar. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaLa exposición a partículas de contaminación ambiental (MP) se encuentra asociada a incrementos en la morbilidad y mortalidad cardiovascular. El estrés oxidativo y la respuesta inflamatoria han sido señalados como partícipes fundamentales en este contexto, aunque los mecanismos subyacentes no se conocen en detalle. El objetivo de este trabajo fue evaluar dicha hipótesis en modelos de exposición aguda in vivo e in vitro, utilizando MP derivado de la combustión del petróleo (ROFA). Se observó una alteración del metabolismo oxidativo y energético cardíaco, junto con una disminución de la reserva contráctil y diastólica. Estos cambios se acompañaron de incrementos en marcadores plasmáticos de estrés oxidativo e inflamación. La reacción inflamatoria producida por ROFA indujo la extravasación de leucocitos, por activación de células endoteliales y mieloides dependiente de TNF-?. Los monocitos circulantes parecerían desempeñar un rol central en los efectos observados, dado que su depleción previene la aparición de marcadores de inflamación local y sistémica. Asimismo, el bloqueo de TNF-? in vivo previno los efectos de ROFA a nivel cardíaco. Estos resultados indican que el estrés oxidativo y la respuesta inflamatoria se encuentran asociados a la exposición a MP, y podrían explicar los efectos adversos reportados sobre el sistema cardiovascular.Doctor de la Universidad de Buenos Aires en Biofísic
The Role of Tumor Necrosis Factor Associated Factors (TRAFs) in Vascular Inflammation and Atherosclerosis
Full text linkTNF receptor associated factors (TRAFs) represent a family of cytoplasmic signaling adaptor proteins that regulate, bundle, and transduce inflammatory signals downstream of TNF- (TNF-Rs), interleukin (IL)-1-, Toll-like- (TLRs), and IL-17 receptors. TRAFs play a pivotal role in regulating cell survival and immune cell function and are fundamental regulators of acute and chronic inflammation. Lately, the inhibition of inflammation by anti-cytokine therapy has emerged as novel treatment strategy in patients with atherosclerosis. Likewise, growing evidence from preclinical experiments proposes TRAFs as potent modulators of inflammation in atherosclerosis and vascular inflammation. Yet, TRAFs show a highly complex interplay between different TRAF-family members with partially opposing and overlapping functions that are determined by the level of cellular expression, concomitant signaling events, and the context of the disease. Therefore, inhibition of specific TRAFs may be beneficial in one condition and harmful in others. Here, we carefully discuss the cellular expression and signaling events of TRAFs and evaluate their role in vascular inflammation and atherosclerosis. We also highlight metabolic effects of TRAFs and discuss the development of TRAF-based therapeutics in the future.Fil: Gissler, Mark Colin. Albert Ludwigs University of Freiburg; AlemaniaFil: Stachon, Peter. Albert Ludwigs University of Freiburg; AlemaniaFil: Wolf, Dennis. Albert Ludwigs University of Freiburg; AlemaniaFil: Marchini, Timoteo Oscar. Albert Ludwigs University of Freiburg; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentin
Pathogenic Role of Air Pollution Particulate Matter in Cardiometabolic Disease: Evidence from Mice and Humans
No full textSignificance: Air pollution is a considerable global threat to human health that dramatically increases the risk for cardiovascular pathologies, such as atherosclerosis, myocardial infarction, and stroke. An estimated 4.2 million cases of premature deaths worldwide are attributable to outdoor air pollution. Among multiple other components, airborne particulate matter (PM) has been identified as the major bioactive constituent in polluted air. While PM-related illness was historically thought to be confined to diseases of the respiratory system, overwhelming clinical and experimental data have now established that acute and chronic exposure to PM causes a systemic inflammatory and oxidative stress response that promotes cardiovascular disease. Recent Advances: A large body of evidence has identified an impairment of redox metabolism and the generation of oxidatively modified lipids and proteins in the lung as initial tissue response to PM. In addition, the pathogenicity of PM is mediated by an inflammatory response that involves PM uptake by tissue-resident immune cells, the activation of proinflammatory pathways in various cell types and organs, and the release of proinflammatory cytokines as locally produced tissue response signals that have the ability to affect organ function in a remote manner. Critical Issues: In the present review, we summarize and discuss the functional participation of PM in cardiovascular pathologies and its risk factors with an emphasis on how oxidative stress, inflammation, and immunity interact and synergize as a response to PM. Future Directions: The impact of PM constituents, doses, and novel anti-inflammatory therapies against PM-related illness is also discussed.Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Zirlik, Andreas. University of Graz; AustriaFil: Wolf, Dennis. University Of Freiburg; Alemani
Inflammatory cell recruitment in cardiovascular disease
Full text linkAtherosclerosis, the main underlying pathology for myocardial infarction and stroke, is a chronic inflammatory disease of middle-sized to large arteries that is initiated and maintained by leukocytes infiltrating into the subendothelial space. It is now clear that the accumulation of pro-inflammatory leukocytes drives progression of atherosclerosis, its clinical complications, and directly modulates tissue-healing in the infarcted heart after myocardial infarction. This inflammatory response is orchestrated by multiple soluble mediators that enhance inflammation systemically and locally, as well as by a multitude of partially tissue-specific molecules that regulate homing, adhesion, and transmigration of leukocytes. While numerous experimental studies in the mouse have refined our understanding of leukocyte accumulation from a conceptual perspective, only a few anti-leukocyte therapies have been directly validated in humans. Lack of tissue-tropism of targeted factors required for leukocyte accumulation and unspecific inhibition strategies remain the major challenges to ultimately translate therapies that modulate leukocytes accumulation into clinical practice. Here, we carefully describe receptor and ligand pairs that guide leukocyte accumulation into the atherosclerotic plaque and the infarcted myocardium, and comment on potential future medical therapies.Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Albert Ludwigs University of Freiburg; Alemania. University Heart Center Freiburg; AlemaniaFil: Mitre, Lucía Sol. Albert Ludwigs University of Freiburg; Alemania. University Heart Center Freiburg; AlemaniaFil: Wolf, Dennis. Albert Ludwigs University of Freiburg; Alemania. University Heart Center Freiburg; Alemani
P2Y6 deficiency limits vascular inflammation and atherosclerosis in mice
No full textObjective - Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y6 (P2Y6) and propagates vascular inflammation by inducing the expression of chemokines such as monocyte chemoattractant protein 1, interleukin-8, or its mouse homologsCCL1 (chemokine [C-C motif] ligand 1)/keratinocyte chemokine, CXCL2 (chemokine [C-X-C motif] ligand 2)/macrophage inflammatory protein 2, and CXCL5 (chemokine [C-X-C motif] ligand 5)/LIX, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1. Thus, P2Y6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Because atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall, we hypothesized a role of P2Y6 in atherogenesis.Fil: Stachon, Peter. Universität Freiburg; AlemaniaFil: Peikert, Alexander. Universität Freiburg; AlemaniaFil: Michel, Nathaly Anto. Universität Freiburg; AlemaniaFil: Hergeth, Sonja. Universität Freiburg; AlemaniaFil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universität Freiburg; AlemaniaFil: Wolf, Dennis. Universität Freiburg; AlemaniaFil: Dufner, Bianca. Universität Freiburg; AlemaniaFil: Hoppe, Natalie. Universität Freiburg; AlemaniaFil: Ayata, Cemil Korcan. Universität Freiburg; AlemaniaFil: Grimm, Melanie. Universität Freiburg; AlemaniaFil: Cicko, Sanja. Universität Freiburg; AlemaniaFil: Schulte, Lisa. Universität Freiburg; AlemaniaFil: Reinöhl, Jochen. Universität Freiburg; AlemaniaFil: Von Zur Muhlen, Constantin. Universität Freiburg; AlemaniaFil: Bode, Christoph. Universität Freiburg; AlemaniaFil: Idzko, Marco. Universität Freiburg; AlemaniaFil: Zirlik, Andreas. Universität Freiburg; Alemani
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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