Enzo Emanuele

Plasma Levels of Soluble Receptor for Advanced Glycation End Products and Coronary Artery Disease in Nondiabetic Men

Objective—The receptor for advanced glycation end products (RAGE) is a cell surface receptor whose signaling pathway has been implicated in atherogenesis. RAGE has an endogenous secretory receptor form, called soluble RAGE (sRAGE), that could exert antiatherogenic effects by acting as a decoy. We sought to determine whether a decreased plasma level of sRAGE could be independently associated with the prevalence of coronary artery disease (CAD) in nondiabetic men. Methods and Results—Plasma levels of sRAGE were determined in 328 nondiabetic male patients with angiographically proved CAD and in 328 age-matched healthy controls. The concentration of sRAGE in plasma was significantly lower (P<0.0001) in CAD cases [median (interquartile range): 966 (658–1372) pg/mL] than in control subjects [1335 (936–1954) pg/mL]. In logistic regression analysis, the multivariate-adjusted odds ratio for the presence of CAD was 6.719 (95% confidence interval, 3.773 to 11.964; P<0.0001) when the lowest quartile of the sRAGE level was compared with the highest quartile. Conclusions—Our findings indicate that low levels of sRAGE in plasma are independently associated with the presence of CAD in nondiabetic men and suggest that sRAGE is one of the clinically important molecules associated with atherosclerosis.

Soluble Receptor for Advanced Glycation End Products: From Disease Marker to Potential Therapeutic Target

The receptor for advanced glycation end products (RAGE) is a cell-bound receptor of the immunoglobulin superfamily which may be activated by a variety of proinflammatory ligands including advanced glycoxidation end products, S100/calgranulins, high mobility group box 1, and amyloid beta-peptide. RAGE has a secretory splice isoform, soluble RAGE (sRAGE), that lacks the transmembrane domain and therefore circulates in plasma. By competing with cell-surface RAGE for ligand binding, sRAGE may contribute to the removal/neutralization of circulating ligands thus functioning as a decoy. Clinical studies have recently shown that higher plasma levels of sRAGE are associated with a reduced risk of coronary artery disease, hypertension, the metabolic syndrome, arthritis and Alzheimers disease. Increasing the production of plasma sRAGE is therefore considered to be a promising therapeutic target that has the potential to prevent vascular damage and neurodegeneration. This review presents the state of the art in the use of sRAGE as a disease marker and discusses the therapeutic potential of targeting sRAGE for the treatment of inflammation-related diseases such as atherosclerosis, arthritis and Alzheimers disease.

Decreased plasma levels of soluble receptor for advanced glycation end-products in patients with essential hypertension

Objectives Advanced glycation end-products (AGE) may cause vascular stiffening by forming crosslinks through the collagen molecule or by interaction with their cellular transductional receptor (RAGE). A secreted isoform of RAGE, termed soluble RAGE (sRAGE), may contribute to the removal/detoxification of AGE by acting as a decoy. Here we studied the plasma sRAGE levels in hypertensive and normotensive human subjects. We also investigated the relationship between blood pressure parameters and plasma sRAGE concentrations. Design A cross-sectional case–control study. Setting and participants The outpatient clinic of a university teaching hospital. Participants were 147 never-treated patients with essential hypertension (87 men and 60 women, aged 50 ± 10 years) and 177 normotensive controls (118 men and 59 women, aged 49 ± 10 years). Main outcome measures Plasma sRAGE levels determined by enzyme-linked immunosorbent assay, systolic blood pressure (SBP), diastolic blood pressure, pulse pressure (PP) and mean arterial pressure. Results The plasma concentration of sRAGE [median (interquartile range)] was 1206 (879–1658) pg/ml in hypertensive subjects and 1359 (999–2198) pg/ml in normotensive controls (P = 0.002). Simple correlation analysis revealed that log-transformed sRAGE levels were inversely correlated with SBP (r = −0.11; P < 0.001) and PP (r = −0.23; P < 0.001). Forward-selection multiple regression analysis revealed that log-transformed sRAGE levels were determined more strongly by PP (F = 3.127, P < 0.001). Conclusions Plasma sRAGE levels are decreased in patients with essential hypertension and are inversely related to PP. Our results raise the possibility that sRAGE may play a role in arterial stiffening and its complications.

Effect of Electrospun Fiber Diameter and Alignment on Macrophage Activation and Secretion of Proinflammatory Cytokines and Chemokines

Macrophage activation can be modulated by biomaterial topography according to the biological scale (micrometric and nanometric range). In this study, we investigated the effect of fiber diameter and fiber alignment of electrospun poly(L-lactic) (PLLA) scaffolds on macrophage RAW 264.7 activation and secretion of proinflammatory cytokines and chemokines at 24 h and 7 days. Macrophages were cultured on four different types of fibrous PLLA scaffold (aligned microfibers, aligned nanofibers, random microfibers, and random nanofibers) and on PLLA film (used as a reference). Substrate topography was found to influence the immune response activated by macrophages, especially in the early inflammation stage. Secretion of proinflammatory molecules by macrophage cells was chiefly dependent on fiber diameter. In particular, nanofibrous PLLA scaffolds minimized the inflammatory response when compared with films and microfibrous scaffolds. The histological evaluation demonstrated a higher number of foreign body giant cells on the PLLA film than on the micro- and nanofibrous scaffolds. In summary, our results indicate that the diameter of electrospun PLLA fibers, rather than fiber alignment, plays a relevant role in influencing in vitro macrophage activation and secretion of proinflammatory molecules.

Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease.

Experimental data have shown an upregulated expression of toll-like receptors, particularly toll-like receptor 4 (TLR4), in neurodegeneration. The Asp299Gly polymorphism of the TLR4 gene has been associated with an attenuated receptor signalling and a blunted inflammatory response. In the present study, we sought to determine whether this common genetic variant could influence susceptibility to late-onset Alzheimers disease (LOAD) in an Italian population sample. A cohort of 277 LOAD patients and 300 cognitively healthy controls were genotyped for the TLR4 Asp299Gly polymorphism using restriction isotyping. The frequency of the minor 299Gly allele was significantly higher in the controls than in the LOAD cases (7.2% versus 3.1%, respectively, P=0.003). Additionally, the frequency of the variant genotypes (Asp/Gly and Gly/Gly) was 13.0% in the controls and 5.4% in LOAD patients (P=0.002). After adjustment for age, gender, and the APOE varepsilon4 carrier status, the odds ratio for the development of LOAD associated with the Asp/Gly and Gly/Gly versus Asp/Asp genotype was 0.37 (95% CI: 0.20-0.69, P=0.002). Our data further support a role for innate immunity in neurodegeneration and give the first evidence that the TLR4 Asp299Gly variant may be protective toward the development of LOAD.

Low-grade endotoxemia in patients with severe autism

The objective of this study was to examine whether levels of endotoxin and other markers of immuno-inflammatory activation are altered in adult patients with severe autism. We determined circulating serum endotoxin levels, its soluble receptor (sCD14), and markers of immuno-inflammatory activation (IL-1beta, IL-6, and IL-10) in 22 adult patients with severe autism and 28 age- and gender-matched healthy controls. Compared with healthy subjects, serum levels of endotoxin were significantly higher in autistic patients and inversely and independently correlated with Socialization scores on the Vineland Adaptive Behavior Scales (VABS) and ADI-R Domain A score (social). Whether increased endotoxin may contribute to the pathophysiology of inflammation and impaired reciprocal social interaction in autism should be further explored in future studies.

Raised plasma nerve growth factor levels associated with early-stage romantic love.

Our current knowledge of the neurobiology of romantic love remains scanty. In view of the complexity of a sentiment like love, it would not be surprising that a diversity of biochemical mechanisms could be involved in the mood changes of the initial stage of a romance. In the present study, we have examined whether the early romantic phase of a loving relationship could be associated with alterations in circulating levels of neurotrophins (NTs). Plasma levels of NGF, BDNF, NT-3 and NT-4 were measured in a total of 58 subjects who had recently fallen in love and compared with those of two control groups, consisting of subjects who were either single or were already engaged in a long-lasting relationship. NGF level was significantly higher (p < 0.001) in the subjects in love [mean (SEM): 227 (14) pg/ml] than in either the subjects with a long-lasting relationship [123 (10) pg/ml] or the subjects with no relationship [149 (12) pg/ml]. Notably, there was also a significant positive correlation between levels of NGF and the intensity of romantic love as assessed with the passionate love scale (r = 0.34; p = 0.007). No differences in the concentrations of other NTs were detected. In 39 subjects in love who-after 12-24 months-maintained the same relationship but were no longer in the same mental state to which they had referred during the initial evaluation, plasma NGF levels decreased and became indistinguishable from those of the control groups. Taken together, these findings suggest that some behavioural and/or psychological features associated with falling in love could be related to raised NGF levels in the bloodstream.

High levels of soluble receptor for advanced glycation end products may be a marker of extreme longevity in humans

at hospital discharge remained unchanged (3%). Patients admitted between 2003 and 2005, although slightly more functionally and cognitively impaired, had fewer comorbid conditions than those hospitalized between 1998 and 2000 (data not shown). In the last few years, some important changes have begun in the care of older people in Italy, the country in Europe with the most older people. First, the mean age of older people hospitalized for acute diseases has increased, reflecting not only the aging of the population, but also the need for intensive medical care for the oldestold. Second, the length of hospitalization has decreased, mainly due to national policy requirements (reduction of the number of admissions and the length of stay to control expenditure). Third, the proportion of cases needing a fulltime caregiver increased, and there were changes in caregiver profile. The aging of the population has led to a greater number of widowed patients and a larger number of people needing a caregiver and thus a greater burden for relatives. Apart from social services (such as nursing home admission), families also sought alternative solutions for the provision of care to their elderly relatives, generating private financial commitments. Descriptive studies of older persons’ perceptions and views about their providers of care are needed.

Behavioral effects of omega-3 fatty acid supplementation in young adults with severe autism: an open label study.

BACKGROUND Pilot findings seem to suggest a potential beneficial effect of omega-3 fatty acid (FA) supplementation on behavioral alterations in children with autism. However, data on the potential benefits of omega-3 supplements in young adults with severe autism are lacking. In the present study, we sought to explore this issue in an open label study. METHODS Nineteen young adults with severe autism (CARS >40), aged 18-40 years, received two fish oil capsules per day [0.93 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) plus 5 mg of vitamin E to avoid lipid peroxidation] for 6 weeks. Subjects were assessed with an ad hoc caregiver questionnaire, the Rossago Behavioral Checklist, for the assessment of behavioral anomalies. RESULTS No significant improvements were observed with regard to the severity and frequency of problematic behaviors either during the active treatment period or during the post-treatment 6-week observation period. Moreover, no effect on the number of episodes and severity of behavior aberrations was observed. CONCLUSIONS Our negative findings do not point toward a major effect of omega-3 FA supplementation on behavioral abnormalities in adults with severe autism. Further studies on larger sample sizes are warranted to shed more light on this important issue.

Exercise attenuates the major hallmarks of aging.

Regular exercise has multi-system anti-aging effects. Here we summarize how exercise impacts the major hallmarks of aging. We propose that, besides searching for novel pharmaceutical targets of the aging process, more research efforts should be devoted to gaining insights into the molecular mediators of the benefits of exercise and to implement effective exercise interventions for elderly people.