Quantifying the relevance of different mediators in the human immune cell network

Immune cells coordinate their efforts for the correct and efficient functioning of the immune system (IS). Each cell type plays a distinct role and communicates with other cell types through mediators such as cytokines, chemokines and hormones, among others, that are crucial for the functioning of the IS and its fine tuning. Nevertheless, a quantitative analysis of the topological properties of an immunological network involving this complex interchange of mediators among immune cells is still lacking. Here we present a method for quantifying the relevance of different mediators in the immune network, which exploits a definition of centrality based on the concept of efficient communication. The analysis, applied to the human immune system, indicates that its mediators significantly differ in their network relevance. We found that cytokines involved in innate immunity and inflammation and some hormones rank highest in the network, revealing that the most prominent mediators of the IS are molecules involved in these ancestral types of defence mechanisms highly integrated with the adaptive immune response, and at the interplay among the nervous, the endocrine and the immune systems.Comment: 10 pages, 3 figure

Correlation analysis reveals the emergence of coherence in the gene expression dynamics following system perturbation

Time course gene expression experiments are a popular means to infer co-expression. Many methods have been proposed to cluster genes or to build networks based on similarity measures of their expression dynamics. In this paper we apply a correlation based approach to network reconstruction to three datasets of time series gene expression following system perturbation: 1) Conditional, Tamoxifen dependent, activation of the cMyc proto-oncogene in rat fibroblast; 2) Genomic response to nutrition changes in D. melanogaster; 3) Patterns of gene activity as a consequence of ageing occurring over a life-span time series (25y–90y) sampled from T-cells of human donors

Changing from a Western to a Mediterranean-style diet does not affect iron or selenium status:Results of the New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE) 1-year randomized clinical trial in elderly Europeans

Background: Mediterranean diets limit red meat consumption and increase intakes of high-phytate foods, a combination that could reduce iron status. Conversely, higher intakes of fish, a good source of selenium, could increase selenium status. Objectives: A 1-y randomized controlled trial [New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe (NU-AGE)] was carried out in older Europeans to investigate the effects of consuming a Mediterraneanstyle diet on indices of inflammation and changes in nutritional status. Methods: Selenium and iron intakes and status biomarkers were measured at baseline and after 1 y in 1294 people aged 65–79 y from 5 European countries (France, Italy, the Netherlands, Poland, and the United Kingdom) who had been randomly allocated either to a Mediterranean-style diet or to remain on their habitual, Western diet. Results: Estimated selenium intakes increased significantly with the intervention group (P < 0.01), but were not accompanied by changes in serum selenium concentrations. Iron intakes also increased (P < 0.001), but there was no change in iron status. However, when stratified by study center, there were positive effects of the intervention on iron status for serum ferritin for participants in Italy (P = 0.04) and France (P = 0.04) and on soluble transferrin receptor (sTfR) for participants in Poland (P < 0.01). Meat intake decreased and fish intake increased to a greater degree in the intervention group, relative to the controls (P < 0.01 for both), but the overall effects of the intervention on meat and fish intakes were mainly driven by data from Poland and France. Changes in serum selenium in the intervention group were associated with greater changes in serum ferritin (P = 0.01) and body iron (P = 0.01), but not sTfR (P = 0.73); there were no study center × selenium status interactions for the iron biomarkers. Conclusions: Consuming a Mediterranean-style diet for 1 y had no overall effect on iron or selenium status, although there were positive effects on biomarkers of iron status in some countries. The NU-AGE trial was registered at clinicaltrials.gov as NCT01754012. Am J Clin Nutr 2019;00:1–12

Associations between Pro- and Anti-Inflammatory Gastro-Intestinal Microbiota, Diet, and Cognitive Functioning in Dutch Healthy Older Adults : The NU-AGE Study

Dietary modulation of the gastro-intestinal microbiota is a potential target in improving healthy ageing and age-related functional outcomes, including cognitive decline. We explored the association between diet, gastro-intestinal microbiota and cognition in Dutch healthy older adults of the 'New dietary strategies addressing the specific needs of the elderly population for healthy aging in Europe' (NU-AGE) study. The microbiota profile of 452 fecal samples from 226 subjects was determined using a 16S ribosomal RNA gene-targeted microarray. Dietary intake was assessed by 7-day food records. Cognitive functioning was measured with an extensive cognitive test battery. We observed a dietary and microbial pro- to anti-inflammatory gradient associated with diets richer in animal- or plant-based foods. Fresh fruits, nuts, seeds and peanuts, red and processed meat and grain products were most strongly associated to microbiota composition. Plant-rich diets containing fresh fruits, nuts, seeds and peanuts were positively correlated with alpha-diversity, various taxa from the Bacteroidetes phylum and anti-inflammatory species, including those related to Faecalibacterium prausnitzii and Eubacterium rectale and E. biforme. Animal product-rich diets associated with pro-inflammatory species, including those related to Ruminococcus gnavus and Collinsella spp.. Cognition was neither associated with microbiota composition nor alpha-diversity. In conclusion, diets richer in animal- and plant-based foods were related to a pro- and anti-inflammatory microbial profile, while cognition was associated with neither.Peer reviewe

Systems medicine of inflammaging

Systems Medicine (SM) can be defined as an extension of Systems Biology (SB) to Clinical-Epidemiological disciplines through a shifting paradigm, starting from a cellular, toward a patient centered framework. According to this vision, the three pillars of SM are Biomedical hypotheses, experimental data, mainly achieved by Omics technologies and tailored computational, statistical and modeling tools. The three SM pillars are highly interconnected, and their balancing is crucial. Despite the great technological progresses producing huge amount of data (Big Data) and impressive computational facilities, the Bio-Medical hypotheses are still of primary importance. A paradigmatic example of unifying Bio-Medical theory is the concept of Inflammaging. This complex phenotype is involved in a large number of pathologies and patho-physiological processes such as aging, age-related diseases and cancer, all sharing a common inflammatory pathogenesis. This Biomedical hypothesis can be mapped into an ecological perspective capable to describe by quantitative and predictive models some experimentally observed features, such as microenvironment, niche partitioning and phenotype propagation. In this article we show how this idea can be supported by computational methods useful to successfully integrate, analyze and model large data sets, combining cross-sectional and longitudinal information on clinical, environmental and omics data of healthy subjects and patients to provide new multidimensional biomarkers capable of distinguishing between different pathological conditions, e.g. healthy versus unhealthy state, physiological versus pathological aging

Gender-specific association of body composition with inflammatory and adipose-related markers in healthy elderly Europeans from the NU-AGE study

Objectives: The aim of this work was to examine the cross-sectional relationship between body composition (BC) markers for adipose and lean tissue and bone mass, and a wide range of specific inflammatory and adipose-related markers in healthy elderly Europeans. Methods: A whole-body dual-energy X-ray absorptiometry (DXA) scan was made in 1121 healthy (65–79 years) women and men from five European countries of the “New dietary strategies addressing the specific needs of elderly population for a healthy aging in Europe” project (NCT01754012) cohort to measure markers of adipose and lean tissue and bone mass. Pro-inflammatory (IL-6, IL-6Rα, TNF-α, TNF-R1, TNF-R2, pentraxin 3, CRP, alpha-1-acid glycoprotein, albumin) and anti-inflammatory (IL-10, TGF-β1) molecules as well as adipose-related markers such as leptin, adiponectin, ghrelin, and resistin were measured by magnetic bead-based multiplex-specific immunoassays and biochemical assays. Results: BC characteristics were different in elderly women and men, and more favorable BC markers were associated with a better adipose-related inflammatory profile, with the exception of skeletal muscle mass index. No correlation was found with the body composition markers and circulating levels of some standard pro- and anti-inflammatory markers like IL-6, pentraxin 3, IL-10, TGF-β1, TNF-α, IL-6Rα, glycoprotein 130, TNF-α-R1, and TNF-α-R2. Conclusions: The association between BC and inflammatory and adipose-related biomarkers is crucial in decoding aging and pathophysiological processes, such as sarcopenia. DXA can help in understanding how the measurement of fat and muscle is important, making the way from research to clinical practice. Key Points: • Body composition markers concordantly associated positively or negatively with adipose-related and inflammatory markers, with the exception of skeletal muscle mass index. • No correlation was found with the body composition markers and circulating levels of some standard pro- and anti-inflammatory markers like IL-6, pentraxin 3, IL-10, TGF-β1, TNF-α, IL-6Rα, gp130, TNF-α-R1, and TNF-α-R2. • Skeletal muscle mass index (SMI) shows a good correlation with inflammatory profile in age-related sarcopenia

Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions : a study on postmenopausal monozygotic twin pairs

MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case-control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54-62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142-3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR-223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes' IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women.Peer reviewe

Postoperative Delirium after elective and emergency surgery: analysis and checking of risk factors. A study protocol

BACKGROUND: Delirum is common in hospitalized elderly patients and may be associated with increased morbidity, length of stay and patient care costs. Delirium (acute confusional state) is defined as an acute disorder of attention and cognition. In elderly patients, delirium is often an early indicator of patho-physiological disturbances. Despite landmark studies dating back to the 1940s, the pathogenesis of Delirium remains poorly understood. Early investigators noted that Delirium was characterized by global cortical dysfunction that was associated predominantly with specific electroencephalographic changes. It's important to understand the risk factors and incidence of Delirium. Some of the risk factors are already identified in literature and can be summarized in the word "VINDICATE" which stands for: Vascular, Infections, Nutrition, Drugs, Injury, Cardiac, Autoimmune, Tumors, Endocrine. Aims of this study are: to re-evaluate the above mentioned clinical risk factors, adding some others selected from literature, and to test, as risk factors, a pattern of some genes associated to cognitive dysfunction and inflammation possibly related to postoperative Delirium. DESIGN: All patients admitted to our Emergency Unit who are meet our inclusion/exclusion criteria will be recruited. The arising of postoperative Delirium will select incidentally two groups (Delirium/non Delirium) and the forward analysis of correlate risk factors will be performed. As in a typical observational case/control study we will consider all the exposure factors to which our population are submitted towards the outcome (presence of Delirium). Our exposures are the following: ASA, Pain (SVS; VAS), Blood gas analysis (pH; Hb; pO2; pCO2), Residence pharmacological therapy (BDZ; hypnotics; narcotic drugs; alcohol; nitrous derivates), Body temperature, Arterial pressure, Heart frequency, Breath frequency, Na, K, Creatinin, Glicemia, Albumin, Hct, White blood cells, Glasgow Coma Scale (GCS), Cognitive state (SPMSQ), Functional state (ADL and IADL), Psychological Distress (HADS), Cumulative Illness Rating Scale (CIRS), Hypotension (classified in: light; moderate and severe and duration), Blood loss (classified in: < 2 lt and > 2 lt), Blood transfusions (< 2 lt and > 2 lt), Quantity of red cells and plasma transfusions, Visual VAS / SVS (timing: I-II-III post-operative day), Red cells and Plasma transfusions, Blood count evaluation and Saturation (O(2)%), Postoperative analgesia (Emilia-Romagna protocol), Presence of malignant tumoral disease, APACHE Score II. Moreover the presence of some relevant genetic polymorphisms will be studied in different genes such as IL-6, IL-10, TNF-alpha, and IL-1 cluster

Changes in Dietary Intake and Adherence to the NU-AGE Diet Following a One-Year Dietary Intervention among European Older Adults—Results of the NU-AGE Randomized Trial

Background: The Mediterranean Diet has been proposed as an effective strategy to reduce inflammaging, a chronic low grade inflammatory status, and thus, to slow down the aging process. We evaluated whether a Mediterranean-like dietary pattern specifically targeting dietary recommendations of people aged over 65 years (NU-AGE diet) could be effective to shift dietary intake of older adults towards a healthful diet. Methods: Adults aged 65–80 years across five EU-centers were randomly assigned to a NU-AGE diet group or control group. The diet group followed one year of NU-AGE dietary intervention specifying consumption of 15 food groups plus the use of a vitamin D supplement. Participants in the diet group received counselling and individually tailored dietary advice, food products and a vitamin D supplement. Dietary intake was assessed by means of seven-day food records at baseline and one-year follow-up. A continuous NU-AGE index (0–160 points) was developed to assess NU-AGE diet adherence. Results: In total 1296 participants were randomized and 1141 participants completed the intervention (571 intervention, 570 control). After one year, the diet group improved mean intake of 13 out of 16 NU-AGE dietary components (p < 0.05), with a significant increase in total NU-AGE index (difference in mean change = 21.3 ± 15.9 points, p < 0.01). Conclusions: The NU-AGE dietary intervention, based on dietary recommendations for older adults, consisting of individual dietary counselling, free healthy foods and a vitamin D supplement, may be a feasible strategy to improve dietary intake in an aging European population