Insight into the biological pathways underlying fibromyalgia by a proteomic approach

Fibromyalgia (FM) is a form of non-articular rheumatism difficult to diagnose and treat because its etiology remains still elusive. Proteomics makes possible the systematic analysis of hundreds of proteins in clinical samples. Consequently, it has become a key tool for finding altered molecular pathways in different diseases. In this context, the present study analyzes changes in the plasma proteome of patients with FM by nanoscale liquid chromatography coupled to tandem mass spectrometry. Deregulated proteins were studied using Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes. Conventional analytical methods were used to validate selected proteins. We found a total of 33 proteins differentially expressed in patients with FM. Haptoglobin and fibrinogen showed the highest FM/control ratio. IPA analysis revealed that the top enriched canonical pathways were acute-phase response signaling, Liver-X Receptor/Retinoid-X Receptor activation, Farnesoid-X Receptor/Retinoid-X Receptor activation, and coagulation and complement systems. The importance of inflammation in FM was corroborated by the increase in erythrocyte sedimentation rate. In conclusion, our results support the existence of a plasma protein signature of FM that involves different biological pathways all of them related to inflammation, and point to haptoglobin and fibrinogen as plausible biomarkercandidates for future studies. Significance: The etiology of fibromyalgia (FM) remains elusive making its diagnosis and treatment difficult. The characterization of the proteome signature of this syndrome will improve its understanding. However, to date proteomic analyses in FM are scarce. The goal of the present work is to analyse, for the first time, changes in plasma protein profiles of patients with FM in comparison to control subjects, using label free relative protein quantification by nanoscale liquid chromatography coupled to tandem mass spectrometry. Our data demonstrate the existence of a common protein signature in the plasma of patients with FM that could explain some of the symptoms associated to this syndrome. The analysis of the 33 proteins differentially expressed corroborates the crucial role of inflammation in the pathogenesis of this syndrome. The interplay of the complement and coagulation cascades contributes to the inflammatory process, while the activation of Liver-X Receptor/Retinoid-X Receptor and Farnesoid-X Receptor/Retinoid-X Receptor could attempt to alleviate it. Finally, we have identified two proteins, haptoglobin and fibrinogen, as potential biomarker-candidates of FM for future studies

La Alpujarra. Paisaje cultural

La presente Unidad Didáctica va dirigida a escolares de educación secundaria siguiendo el currículo básico del Real Decreto 1631/2006, de 29 de diciembre, por el que se establecen las enseñanzas mínimas correspondientes a la Educación Secundaria Obligatoria, (BOE de 5-1-2007) y Orden de 10-8-2007, por la que se desarrolla el currículo correspondiente a la Educación Secundaria Obligatoria en Andalucía. (BOJA de 30-8-2007), con lo cual las actividades se adaptan al alumnado cuya edad esté comprendida entre 12 y 16 años. La UD debe entenderse como una herramienta de formación personal, y de adquisición de conocimientos relacionados con el territorio en el que viven, con el objetivo de proporcionar autonomía personal para acceder a aprendizajes futuros y facilitadora del desarrollo integral de la persona.Las actividades no deben restringirse a una acción puntual, ni considerarlas como una actividad extraescolar y lúdica, ya que el objetivo es incluir dichas temáticas relacionadas con el territorio de la Alpujarra en el temario general del curso y de manera transversal en las diferentes asignaturas.La Unidad Didáctica “La Alpujarra, Paisaje Cultural” se ha realizado en el marco del proyecto europeo “MEditerranean MOuntainous LAndscapes. una aproximación histórica al patrimonio cultural basada en los agrosistemas tradicionales” financiado por el Séptimo Programa Marco de Investigación, Desarrollo Tecnológico y Demostración de la Unión Europea, bajo el acuerdo de subvención nº613265

Salmonella Typhimurium Type III Secretion Effectors Stimulate Innate Immune Responses in Cultured Epithelial Cells

Recognition of conserved bacterial products by innate immune receptors leads to inflammatory responses that control pathogen spread but that can also result in pathology. Intestinal epithelial cells are exposed to bacterial products and therefore must prevent signaling through innate immune receptors to avoid pathology. However, enteric pathogens are able to stimulate intestinal inflammation. We show here that the enteric pathogen Salmonella Typhimurium can stimulate innate immune responses in cultured epithelial cells by mechanisms that do not involve receptors of the innate immune system. Instead, S. Typhimurium stimulates these responses by delivering through its type III secretion system the bacterial effector proteins SopE, SopE2, and SopB, which in a redundant fashion stimulate Rho-family GTPases leading to the activation of mitogen-activated protein (MAP) kinase and NF-κB signaling. These observations have implications for the understanding of the mechanisms by which Salmonella Typhimurium induces intestinal inflammation as well as other intestinal inflammatory pathologies

Homérica: estudiar y vivir el mundo griego II

Depto. de Filología ClásicaFac. de FilologíaFALSEsubmitte

Cytolethal Distending Toxin: Limited Damage as a . . .

the morphological changes associated with this activity. Since then, similar activities have been reported in other unrelated Gram-negative pathogenic bacteria such as strains of E. coli [4], Shigella dysenteriae [5], Haemophilus ducreyi [6], Actinobacillus actinomycetemcomitans [7] and Helicobacter hepaticus [8]. The recently released Salmonella enterica serovar Typhi genome sequence has also revealed the presence of a gene encoding at least one component of the CDT toxin [9]. CDT toxins are thus emerging as conserved virulence factors in several pathogenic bacteria. Molecular and genetic bases of CDT activity The cloning and characterization of the structural genes of different CDTs constituted a major advancement in our understanding of these toxins. Since the initial cloning of the cdt locus from two different E. coli clinical isolates [10,11], the genes responsible for CDT activity in various CDTproducing bacteria have been cloned and sequenced [5--8,12,13]. In all cases, t

CdtA, CdtB, and CdtC form a tripartite complex that is required for cytolethal distending toxin activity. Infect Immun 69

Campylobacter jejuni encodes a cytolethal distending toxin (CDT) that causes cells to arrest in the G 2/M transition phase of the cell cycle. Highly related toxins are also produced by other important bacterial pathogens. CDT activity requires the function of three genes: cdtA, cdtB, and cdtC. Recent studies have established that CdtB is the active subunit of CDT, exerting its effect as a nuclease that damages the DNA and triggers cell cycle arrest. Microinjection of CdtB into target cells led to G 2/M arrest and cytoplasmic distention, in a manner indistinguishable from that caused by CDT treatment. Despite this progress, nothing is known about the composition of the CDT holotoxin or the function of CdtA and CdtC. We show here that, when applied individually, purified CdtA, CdtB, or CdtC does not exhibit toxic activity. In contrast, CdtA, CdtB, and CdtC when combined, interact with one another to form an active tripartite holotoxin that exhibits full cellular toxicity. CdtA has a domain that shares similarity with the B chain of ricin-related toxins. We therefore proposed that CDT is a tripartite toxin composed of CdtB as the enzymatically active subunit and of CdtA and CdtC as the heterodimeric B subunit required for the delivery of CdtB. Campylobacter jejuni is the leading cause of bacterial foodborne illness in the United States and Europe (21). Despite its great importance in human health, relatively little is know

Salmonella enterica Serovar Typhimurium Pathogenicity Island 1-Encoded Type III Secretion System Translocases Mediate Intimate Attachment to Nonphagocytic Cells▿ †

Delivery of bacterial proteins into mammalian cells by type III secretion systems (TTSS) is thought to require the intimate association of bacteria with target cells. The molecular bases of this intimate association appear to be different in different bacteria involving TTSS components, as well as surface determinants not associated with TTSS. We show here that the protein translocases SipB, SipC, and SipD of the Salmonella enterica serovar Typhimurium pathogenicity island 1 (SPI-1)-encoded TTSS are required for the intimate association of these bacteria with mammalian cells. S. Typhimurium mutant strains lacking any of the translocases were defective for intimate attachment. Immunofluorescence microscopy showed that SipD is present on the bacterial surface prior to bacterial contact with host cells. In contrast, SipB and SipC were detected on the bacterial surface only subsequent to bacterial contact with the target cell. We conclude that the coordinated deployment and interaction between the protein translocases mediate the SPI-1 TTSS-dependent intimate association of S. Typhimurium with host cells

A MyD88-Deficient Mouse Model Reveals a Role for Nramp1 in Campylobacter jejuni Infection

Campylobacter jejuni is a major worldwide cause of enteric illnesses. Adult immunocompetent mice are not susceptible to C. jejuni infection. However, we show here that mice deficient in the adaptor protein myeloid differentiation factor 88 (MyD88), which is required for signaling through most Toll-like receptors, can be stably colonized by C. jejuni but not by isogenic derivatives carrying mutations in known virulence genes. We also found that Nramp1 deficiency increases the mouse susceptibility to C. jejuni infection when administered systemically. These results indicate that MyD88-deficient mice could be a useful model to study C. jejuni colonization and reveal a potential role for Nramp1 in the control of this bacterial pathogen

Hydroxytyrosol as a Promising Ally in the Treatment of Fibromyalgia

Fibromyalgia (FM) is a chronic and highly disabling syndrome, which is still underdiagnosed, with controversial treatment. Although its aetiology is unknown, a number of studies have pointed to the involvement of altered mitochondrial metabolism, increased oxidative stress and inflammation. The intake of extra virgin olive oil, and particularly of one of its phenolic compounds, hydroxytyrosol (HT), has proven to be protective in terms of redox homeostatic balance and the reduction of inflammation. In this context, using a proteomic approach with nanoscale liquid chromatography coupled to tandem mass spectrometry, the present study analysed: (i) Changes in the proteome of dermal fibroblasts from a patient with FM versus a healthy control, and (ii) the effect of the treatment with a nutritional relevant dose of HT. Our results unveiled that fibroblast from FM show a differential expression in proteins involved in the turnover of extracellular matrix and oxidative metabolism that could explain the inflammatory status of these patients. Moreover, a number of these proteins results normalized by the treatment with HT. In conclusion, our results support that an HT-enriched diet could be highly beneficial in the management of FM