Retinal Alterations Predict Early Prodromal Signs of Neurodegenerative Disease.

Neurodegenerative diseases are an increasingly common group of diseases that occur late in life with a significant impact on personal, family, and economic life. Among these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the major disorders that lead to mild to severe cognitive and physical impairment and dementia. Interestingly, those diseases may show onset of prodromal symptoms early after middle age. Commonly, the evaluation of these neurodegenerative diseases is based on the detection of biomarkers, where functional and structural magnetic resonance imaging (MRI) have shown a central role in revealing early or prodromal phases, although it can be expensive, time-consuming, and not always available. The aforementioned diseases have a common impact on the visual system due to the pathophysiological mechanisms shared between the eye and the brain. In Parkinson's disease, α-synuclein deposition in the retinal cells, as well as in dopaminergic neurons of the substantia nigra, alters the visual cortex and retinal function, resulting in modifications to the visual field. Similarly, the visual cortex is modified by the neurofibrillary tangles and neuritic amyloid ß plaques typically seen in the Alzheimer's disease brain, and this may reflect the accumulation of these biomarkers in the retina during the early stages of the disease, as seen in postmortem retinas of AD patients. In this light, the ophthalmic evaluation of retinal neurodegeneration could become a cost-effective method for the early diagnosis of those diseases, overcoming the limitations of functional and structural imaging of the deep brain. This analysis is commonly used in ophthalmic practice, and interest in it has risen in recent years. This review will discuss the relationship between Alzheimer's disease and Parkinson's disease with retinal degeneration, highlighting how retinal analysis may represent a noninvasive and straightforward method for the early diagnosis of these neurodegenerative diseases.

Classical and Innovative Evidence for Therapeutic Strategies in Retinal Dysfunctions.

The human retina is a complex anatomical structure that has no regenerative capacity. The pathogenesis of most retinopathies can be attributed to inflammation, with the activation of the inflammasome protein platform, and to the impact of oxidative stress on the regulation of apoptosis and autophagy/mitophagy in retinal cells. In recent years, new therapeutic approaches to treat retinopathies have been investigated. Experimental data suggest that the secretome of mesenchymal cells could reduce oxidative stress, autophagy, and the apoptosis of retinal cells, and in turn, the secretome of the latter could induce changes in mesenchymal cells. Other studies have evidenced that noncoding (nc)RNAs might be new targets for retinopathy treatment and novel disease biomarkers since a correlation has been found between ncRNA levels and retinopathies. A new field to explore is the interaction observed between the ocular and intestinal microbiota; indeed, recent findings have shown that the alteration of gut microbiota seems to be linked to ocular diseases, suggesting a gut-eye axis. To explore new therapeutical strategies for retinopathies, it is important to use proper models that can mimic the complexity of the retina. In this context, retinal organoids represent a good model for the study of the pathophysiology of the retina.

Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations.

Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss of neuronal functions and structures. Despite having different genetic backgrounds and etiology, in recent years, many studies have highlighted a point of convergence in the mechanisms leading to neurodegeneration: mitochondrial dysfunction and oxidative stress have been observed in different pathologies, and their detrimental effects on neurons contribute to the exacerbation of the pathological phenotype at various degrees. In this context, increasing relevance has been acquired by antioxidant therapies, with the purpose of restoring mitochondrial functions in order to revert the neuronal damage. However, conventional antioxidants were not able to specifically accumulate in diseased mitochondria, often eliciting harmful effects on the whole body. In the last decades, novel, precise, mitochondria-targeted antioxidant (MTA) compounds have been developed and studied, both in vitro and in vivo, to address the need to counter the oxidative stress in mitochondria and restore the energy supply and membrane potentials in neurons. In this review, we focus on the activity and therapeutic perspectives of MitoQ, SkQ1, MitoVitE and MitoTEMPO, the most studied compounds belonging to the class of MTA conjugated to lipophilic cations, in order to reach the mitochondrial compartment.

Sex/Gender-Specific Imbalance in CVD: Could Physical Activity Help to Improve Clinical Outcome Targeting CVD Molecular Mechanisms in Women?

In the last two decades, new insights have been gained regarding sex/gender-related differences in cardiovascular disease (CVD). CVD represents the leading cause of death worldwide in both men and women, accounting for at least one-third of all deaths in women and half of deaths in women over 50 years in developing countries. Important sex-related differences in prevalence, presentation, management, and outcomes of different CVDs have been recently discovered, demonstrating sex/gender-specific pathophysiologic features in the presentation and prognosis of CVD in men and women. A large amount of evidence has highlighted the role of sex hormones in protecting women from CVDs, providing an advantage over men that is lost when women reach the menopause stage. This hormonal-dependent shift of sex-related CVD risk consequently affects the overall CVD epidemiology, particularly in light of the increasing trend of population aging. The benefits of physical activity have been recognized for a long time as a powerful preventive approach for both CVD prevention and aging-related morbidity control. Exercise training is indeed a potent physiological stimulus, which reduces primary and secondary cardiovascular events. However, the underlying mechanisms of these positive effects, including from a sex/gender perspective, still need to be fully elucidated. The aim of this work is to provide a review of the evidence linking sex/gender-related differences in CVD, including sex/gender-specific molecular mediators, to explore whether sex- and gender-tailored physical activity may be used as an effective tool to prevent CVD and improve clinical outcomes in women.

Clinical perspectives of TRAIL: insights into central nervous system disorders.

The TNF-related apoptosis inducing ligand TRAIL is a member of the TNF superfamily that has been firstly studied and evaluated for its anti-cancer activity, and the insights into its biology have already led to the identification of several TRAIL-based anticancer strategies with strong clinical therapeutic potentials. Nonetheless, the TRAIL system is far more complex and it can lead to a wider range of biological effects other than the ability of inducing apoptosis in cancer cells. By virtue of the different receptors and the different signalling pathways involved, TRAIL plays indeed a role in the regulation of different processes of the innate and adaptive immune system and this feature makes it an intriguing molecule under consideration in the development/progression/treatment of several immunological disorders. In this context, central nervous system represents a peculiar anatomic site where, despite its "status" of immune-privileged site, both innate and adaptive inflammatory responses occur and are involved in several pathological conditions. A number of studies have evaluated the role of TRAIL and of TRAIL-related pathways as pro-inflammatory or protective stimuli, depending on the specific pathological condition, confirming a twofold nature of this molecule. In this light, the aim of this review is to summarize the main preclinical evidences of the potential/involvement of TRAIL molecule and TRAIL pathways for the treatment of central nervous system disorders and the key suggestions coming from their assessment in preclinical models as proof of concept for future clinical studies.

Vaginal Lactoferrin Modulates PGE2, MMP-9, MMP-2, and TIMP-1 Amniotic Fluid Concentrations.

Inflammation plays an important role in pregnancy, and cytokine and matrix metalloproteases (MMPs) imbalance has been associated with premature rupture of membranes and increased risk of preterm delivery. Previous studies have demonstrated that lactoferrin (LF), an iron-binding protein with anti-inflammatory properties, is able to decrease amniotic fluid (AF) levels of IL-6. Therefore, we aimed to evaluate the effect of vaginal LF administration on amniotic fluid PGE2 level and MMP-TIMP system in women undergoing genetic amniocentesis. One hundred and eleven women were randomly divided into controls (n = 57) or treated with LF 4 hours before amniocentesis (n = 54). Amniotic fluid PGE2, active MMP-9 and MMP-2, and TIMP-1 and TIMP-2 concentrations were determined by commercially available assays and the values were normalized by AF creatinine concentration. PGE2, active MMP-9, and its inhibitor TIMP-1 were lower in LF-treated group than in controls (p < 0.01, p < 0.005, and p < 0.001, resp.). Conversely, active MMP-2 (p < 0.0001) and MMP-2/TIMP-2 molar ratio (p < 0.001) were increased, whilst TIMP-2 was unchanged. Our data suggest that LF administration is able to modulate the inflammatory response following amniocentesis, which may counteract cytokine and prostanoid imbalance that leads to abortion. This trial is registered with Clinical Trial number NCT02695563.

Soluble TRAIL is present at high concentrations in seminal plasma and promotes spermatozoa survival.

The expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL(TNFSF10)) and of its receptors (TRAILR1, TRAILR2, TRAILR3, and TRAILR4) have been documented in testis, but the presence of soluble TRAIL in seminal fluid, as well as the potential physiopathological role of the TRAIL/TRAILR system in spermatozoa, has not been previously investigated. Male donors (n=123) among couples presenting for infertility evaluation were consecutively enrolled in this study. The presence of soluble TRAIL was analyzed in seminal samples by ELISA, while the surface expression of TRAIL receptors was investigated by flow cytometry. High levels of soluble TRAIL were detected in seminal plasma (median, 11 621 pg/ml and mean±s.d., 13 371±8367 pg/ml) and flow cytometric analysis revealed a variable expression of TRAIL receptors in the sperm cellular fraction among different subjects. In addition, the effect of physiologically relevant concentrations of recombinant TRAIL was investigated on survival and motility of spermatozoa. Of interest, the in vitro exposure of capacitated spermatozoa to recombinant TRAIL (10 ng/ml) significantly preserved their overall survival. Therefore, the present study demonstrates for the first time the presence of elevated levels of the anti-inflammatory cytokine TRAIL in seminal fluids. Moreover, the demonstration that recombinant TRAIL promotes spermatozoa survival after capacitation suggests potential therapeutic implications.

Characterization Methods for Nanoparticle-Skin Interactions: An Overview.

Research progresses have led to the development of different kinds of nanoplatforms to deliver drugs through different biological membranes. Particularly, nanocarriers represent a precious means to treat skin pathologies, due to their capability to solubilize lipophilic and hydrophilic drugs, to control their release, and to promote their permeation through the stratum corneum barrier. A crucial point in the development of nano-delivery systems relies on their characterization, as well as in the assessment of their interaction with tissues, in order to predict their fate under in vivo administration. The size of nanoparticles, their shape, and the type of matrix can influence their biodistribution inside the skin strata and their cellular uptake. In this respect, an overview of some characterization methods employed to investigate nanoparticles intended for topical administration is presented here, namely dynamic light scattering, zeta potential, scanning and transmission electron microscopy, X-ray diffraction, atomic force microscopy, Fourier transform infrared and Raman spectroscopy. In addition, the main fluorescence methods employed to detect the in vitro nanoparticles interaction with skin cell lines, such as fluorescence-activated cell sorting or confocal imaging, are described, considering different examples of applications. Finally, recent studies on the techniques employed to determine the nanoparticle presence in the skin by ex vivo and in vivo models are reported.

Activation of the p53 pathway induces α-smooth muscle actin expression in both myeloid leukemic cells and normal macrophages.

A range of cell types of mesenchymal origin express α-smooth muscle actin (α-SMA), a protein that plays a key role in controlling cell motility and differentiation along the fibrocyte and myofibroblast lineages. Although α-SMA is often expressed in stromal cells associated to a variety of cancers including hematological malignancies, up to now the role of anti-cancer drugs on α-SMA has not been deeply investigated. In this study, we demonstrated that Nutlin-3, the small molecule inhibitor of the MDM2/p53 interactions, significantly up-regulated the mRNA and protein levels of α-SMA in normal macrophages as well as in p53(wild-type) but not in p53(mutated/null) myeloid leukemic cells. The p53-dependence of α-SMA up-regulation induced by Nutlin-3 was demonstrated in experiments performed with siRNA for p53. Of note, Nutlin-3 mediated up-regulation of α-SMA in OCI leukemic cells was accompanied by cell adhesion to plastic substrate and by reduced cell migratory response in transwell assays. Notably, the role of α-SMA induction in the modulation of myeloid cell migration was clearly documented in α-SMA gene knockdown experiments. In addition, Nutlin-3 significantly up-regulated α-SMA expression in primary endothelial cells, but not in fibroblasts and mesenchymal stem cells (MSC). Conversely, transforming growth factor-ß1 up-regulated α-SMA in fibroblasts and MSC, but not in macrophages and endothelial cells. Taken together, these data indicate that Nutlin-3 is a potent inducer of α-SMA in both normal and leukemic myeloid cells as well as in endothelial cells.

Pegylated TRAIL retains anti-leukemic cytotoxicity and exhibits improved signal transduction activity with respect to TRAIL.

To improve the pharmacokinetic profile of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) an N-terminal specific pegylation was performed to generate pegylated TRAIL (PEG-TRAIL). In in vitro experiments, we found that although PEG-TRAIL was slightly less efficient than recombinant TRAIL in promoting leukemic cell apoptosis, it showed an improved ability to promote migration of bone-marrow mesenchymal stem cells and to elicit the ERK1/2 intracellular signal transduction pathway. Overall, these data suggest that TRAIL pegylation retains, or even enhances, the biological activities of TRAIL relevant for its therapeutic applications.

New Applications of JAK/STAT Inhibitors in Pediatrics: Current Use of Ruxolitinib.

Janus kinases (JAK) are a family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that transduce cytokine-mediated signals through the JAK-STAT metabolic pathway. These kinases act by regulating the transcription of specific genes capable of inducing biological responses in several immune cell subsets. Inhibition of Janus kinases interferes with the JAK-STAT signaling pathway. Besides being used in the treatment of cancer and inflammatory diseases, in recent years, they have also been used to treat inflammatory conditions, such as graft-versus-host disease (GVHD) and cytokine release syndrome as complications of allogeneic hematopoietic stem cell transplantation and cell therapy. Recently, the FDA approved the use of ruxolitinib, a JAK1/2 inhibitor, in the treatment of acute steroid-refractory GVHD (SR-aGVHD), highlighting the role of JAK inhibition in this immune deregulation. Ruxolitinib was initially used to treat myelofibrosis and true polycythemia in a high-dose treatment and caused hematological toxicity. Since a lower dosage often could not be effective, the use of ruxolitinib was suspended. Subsequently, ruxolitinib was evaluated in adult patients with SR-aGVHD and was found to achieve a rapid and effective response. In addition, its early low-dose use in pediatric patients affected by GVHD has proved effective, safe, and reasonably preventive. The review aims to describe the potential properties of ruxolitinib to identify new therapeutic strategies.

Trail down-regulates the release of osteoprotegerin (OPG) by primary stromal cells.

The soluble member of the TNF-R superfamily osteoprotegerin (OPG) is abundantly released under basal conditions by both mesenchymal stem cells (MSC) and fibroblasts and by endothelial cells upon stimulation with inflammatory cytokines. Since MSC, fibroblasts and endothelial cells represent key elements of the normal and tumor microenvironment and express detectable levels of surface TRAIL receptors, we investigated the effect of TRAIL on OPG release. Unexpectedly, recombinant TRAIL decreased the spontaneous OPG release in all cell types examined. Moreover, TRAIL decreased OPG release also in stromal cells co-cultured with lymphoma cells and counteracted the OPG induction by TN-alpha in HUVEC and MSC. Such down-regulation was not due to a masking effect in the ELISA quantification of the OPG released in the culture supernatants due to binding of OPG to its ligands (TRAIL and RANKL), as demonstrated by competition experiments with recombinant TRAIL and by the lack of RANKL release/induction. In addition, OPG down-regulation was not due to induction of cytotoxic effects by TRAIL, since the degree of apoptosis in response to TRAIL was negligible in all primary cell types. With regards to the possible molecular mechanism accounting for the down-regulation of OPG release by TRAIL, we found that treatment of MSC with TRAIL significantly decreased the phosphorylation levels of p38/MAPK. There is a suggestion that this pathway is involved in the stabilization of OPG mRNA. In this respect, the ability of TRAIL to decrease the release of OPG, in the absence of cell cytotoxicity, was mimicked by the p38/MAPK inhibitor SB203580.

The IMMENSE Study: The Interplay Between iMMune and ENdothelial Cells in Mediating Cardiovascular Risk in Systemic Lupus Erythematosus.

Patients with systemic lupus erythematosus (SLE) have a significant increase in cardiovascular (CV) risk although they display a preserved number of circulating angiogenic CD3+CD31+CXCR4+ T cells (Tang), a subpopulation of T cells which promotes repair of damaged endothelium. This happens due to the concomitant expansion of a Tang subset with immunosenescent features, such as the loss of CD28. Therefore, the aim of this study was to elucidate the interplay between Tang subpopulations and endothelial cells in a group of young SLE patients without previous cardiovascular events. Twenty SLE female patients and 10 healthy controls (HCs) were recruited. Flow cytometric analysis of endothelial progenitor cells (EPCs) and Tang subsets were performed and serum levels of interleukin (IL)-6, -8, matrix metalloproteinase (MMP)-9 and interferon (IFN)-γ were measured. Human umbilical vein endothelial cells (HUVECs) proliferation and pro-inflammatory phenotype in response to subjects' serum stimulation were also evaluated. Results showed that the percentage of Tang and EPC subsets was reduced in SLE patients compared with HCs, with a marked increase of senescent CD28null cells among Tang subset. SLE disease activity index-2000 (SLEDAI-2K) was inversed related to Tang cells percentage. Furthermore, IL-8 serum levels were directly correlated with the percentage of Tang and inversely related to the CD28null Tang subsets. We indirectly evaluated the role of the Tang subset on the endothelium upon stimulation with serum from subjects with a low percentage of Tang CD3+ cells in HUVECs. HUVECs displayed pro-inflammatory phenotype with up-regulation of mRNA for IL-6, intercellular adhesion molecule (ICAM)-1 and endothelial leukocyte adhesion molecule (ELAM)-1. Cell proliferation rate was directly related to IL-8 serum levels and EPC percentage. In highly selected young SLE patients without previous CV events, we found that the deterioration of Tang compartment is an early event in disease course, preceding the development of an overt cardiovascular disease and potentially mediated by SLE-specific mechanisms. The overcome of the CD28null subset exerts detrimental role over the Tang phenotype, where Tang could exert an anti-inflammatory effect on endothelial cells and might orchestrate via IL-8 the function of EPCs, ultimately modulating endothelial proliferation rate.

The soluble terminal complement complex (SC5b-9) up-regulates osteoprotegerin expression and release by endothelial cells: implications in rheumatoid arthritis.

OBJECTIVE: Complement activation products contribute to a large number of inflammatory diseases, including RA. We have investigated whether osteoprotegerin (OPG) may concur with the soluble terminal complement complex (SC5b-9) to the inflammatory cascade characterizing RA. METHODS: Levels of SC5b-9 and OPG in the plasma and SF of patients with active RA were determined by ELISA. The presence of SC5b-9 and OPG in RA synovial lesions was analysed by immunohistochemistry. Cultured endothelial cells were used for in vitro leucocyte/endothelial cell adhesion assays. In addition, endothelial cells were exposed to SC5b-9 in order to evaluate the effects on the production of OPG protein, as well as the activation of the OPG promoter. RESULTS: Patients affected by active RA are characterized by elevated levels of both SC5b-9 and OPG in plasma and/or SF. Of note, we have observed a co-localization of SC5b-9 and OPG in endothelial cells of post-capillary venules of RA synovial lesions. Data on endothelial cell cultures showed that exposure to SC5b-9 induced the up-regulation of OPG expression/release, stimulating the transcriptional activity of the OPG promoter, and synergized with TNF-alpha in up-regulating OPG production. CONCLUSIONS: Our findings demonstrate that SC5b-9 induces OPG production by endothelial cells and we propose that the SC5b-9-mediated up-regulation of OPG may be an important mechanism whereby complement contributes in promoting and/or enhancing the inflammation in RA.

Antiangiogenic activity of the MDM2 antagonist nutlin-3.

Nutlin-3, a nongenotoxic activator of the p53 pathway, dose-dependently (range 0.1 to 10 micromol/L) inhibited the formation of capillaries in an in vivo matrigel assay, as well as the formation of capillary-like structures in an in vitro coculture system composed of endothelial cells surrounded by fibroblasts. In contrast to the chemotherapeutic agent doxorubicin, nutlin-3 showed no induction of apoptosis in vitro either in the cocultures or in isolated vascular endothelial cells, even when used at the highest concentration (10 micromol/L). However, treatment with pharmacological inhibitors of the nuclear factor kappaB and phosphatidylinositol 3-kinase/Akt pathways sensitized endothelial cells to nutlin-3-induced apoptosis. Although nutlin-3 and doxorubicin induced a comparable p53 accumulation in endothelial cells, nutlin-3 was significantly more efficient than doxorubicin in upregulating the p53 target genes CDKN1A/p21, MDM2, and GDF-15, as well as in inhibiting cell cycle progression. However, the predominant in vitro effect of nutlin-3 was its strong antimigratory activity observed at concentrations significantly lower (0.1 micromol/L) than those required to inhibit endothelial cell cycle progression. Taken together, our data suggest that the antiangiogenic activity of nutlin-3 observed in vivo was mainly attributable to inhibition of endothelial cell migration, to some extent attributable to cell cycle arrest, and to a lesser extent attributable to induction of apoptosis.

Combined treatment of CpG-oligodeoxynucleotide with Nutlin-3 induces strong immune stimulation coupled to cytotoxicity in B-chronic lymphocytic leukemic (B-CLL) cells.

We have investigated the effect of combined treatment with CpG-oligodeoxynucleotide (CpG-ODN) plus Nutlin-3, a small molecule inhibitor of the murine double minute 2/p53 interaction, on the immune activation, cell cycle progression, and apoptosis of peripheral blood B chronic lymphocytic leukemia (B-CLL) cells. CpG-ODN induced a robust up-regulation of immune activation markers (CD54, CD69, CD80, CD86, MHC-II) in Zap70high and Zap70low B-CLL samples. Although cotreatment of B-CLL cells with CpG-ODN + Nutlin-3 did not interfere with such immune activation, CpG-ODN potentiated the Nutlin-3-mediated induction of the death receptors CD95 and TRAIL receptor 2. Importantly, treatment with CpG-ODN did not interfere with the ability of Nutlin-3 to inhibit cell cycle progression and to induce apoptosis. Thus, a therapeutic regimen including CpG-ODN plus Nutlin-3 might have the advantage to preserve the immune activation of B-CLL cells while restraining the prosurvival/proliferative potential of CpG-ODN treatment.

Oxidative stress: role of physical exercise and antioxidant nutraceuticals in adulthood and aging.

Physical exercise is considered to be one of the beneficial factors of a proper lifestyle and is nowadays seen as an indispensable element for good health, able to lower the risk of disorders of the cardiovascular, endocrine and osteomuscular apparatus, immune system diseases and the onset of potential neoplasms. A moderate and programmed physical exercise has often been reported to be therapeutic both in the adulthood and in aging, since capable to promote fitness. Regular exercise alleviates the negative effects caused by free radicals and offers many health benefits, including reduced risk of all-cause mortality, sarcopenia in the skeletal muscle, chronic disease, and premature death in elderly people. However, physical performance is also known to induce oxidative stress, inflammation, and muscle fatigue. Many efforts have been carried out to identify micronutrients and natural compounds, also known as nutraceuticals, able to prevent or attenuate the exercise-induced oxidative stress and inflammation. The aim of this review is to discuss the benefits deriving from a constant physical activity and by the intake of antioxidant compounds to protect the body from oxidative stress. The attention will be focused mainly on three natural antioxidants, which are quercetin, resveratrol and curcumin. Their properties and activity will be described, as well as their benefits on physical activity and on aging, which is expected to increase through the years and can get favorable benefits from a constant exercise activity.

Inherited genetic predispositions in F13A1 and F13B genes predict abdominal adhesion formation: identification of gender prognostic indicators.

Abdominal adhesions (AA) account for the most common complication of peritoneal surgery with bowel obstruction being the severest problem in the absence of effective predicting biomarkers. Anti-AA-barriers or adhesiolysis did not completely prevent bowel obstruction, although there is evidence they might reduce related complications requiring reoperation. In addition, gender-related predispositions have not been adequately investigated. We explored the role of coagulation Factor XIII (F13A1 and F13B subunit-genes) in patients following laparotomy, mostly median/lower median incision line. Globally, 426 patients (54%,♀), were PCR-SNP-genotyped for FXIIIA V34L (rs5985), FXIIIA P564L (rs5982), FXIIIA Y204F (rs3024477) and FXIIIB H95R (rs6003). Patients' clinical phenotypes were: Group-A (n = 212), those who developed AA, and 55.2% of them developed bowel obstruction (subgroup-A1), the remaining were subgroup-A2; Group B (n = 214) were those who did not develop AA (subgroup-B1; 53.3%) or symptoms/complications (subgroup-B2). Among different laparotomy, colon surgery associated with AA at a major extent (OR = 5.1; 3.24-7.8; P < 0.0001) with different gender scores (♀OR = 5.33; 2.32-12.23; P < 0.0001 and ♂OR = 3.44; 1.58-7.49; P < 0.0001). Among SNPs, P564L (OR = 4.42; 1.45-13.4; P = 0.008) and Y204F (OR = 7.78; 1.62-37.3; P = 0.01) significantly predicted bowel obstruction and survival-analyses yielded interesting gender distinctions (♀HR = 5.28; 2.36-11.8; P = 0.00005; ♂HR = 2.22; 1.31-3.85; P = 0.0034). Active compounds preventing AA belong to the anticoagulant/fibrinolysis areas, suggesting them candidate investigation targets. We identified novel prognostic markers to predict AA/bowel obstruction giving insights to design novel therapeutic and gender prevention programs.

Effects of Hypoxia and Bed Rest on Markers of Cardiometabolic Risk: Compensatory Changes in Circulating TRAIL and Glutathione Redox Capacity.

In chronic diseases, hypoxia and physical inactivity are associated with atherosclerosis progression. In contrast, a lower mortality from coronary artery disease and stroke is observed in healthy humans residing at high altitude in hypoxic environments. Eleven young, male volunteers completed the following 10-day campaigns in a randomized order: hypoxic ambulatory, hypoxic bed rest and normoxic bed rest. Before intervention, subjects were evaluated in normoxic ambulatory condition. Normobaric hypoxia was achieved in a hypoxic facility simulating 4000 m of altitude. Following hypoxia, either in bed rest or ambulatory condition, markers of cardiometabolic risk shifted toward a more atherogenic pattern consisting of: (a) lower levels of total HDL cholesterol and HDL2 sub-fraction and decreased hepatic lipase; (b) activation of systemic inflammation, as determined by C-reactive protein and serum amyloid A; (c) increased plasma homocysteine; (d) decreased delta-5 desaturase index in cell membrane fatty acids, a marker of insulin sensitivity. Bed rest and hypoxia additively decreased total HDL and delta-5 desaturase index. In parallel to the pro-atherogenic effects, hypoxia activated selected anti-atherogenic pathways, consisting of increased circulating TNF-related apoptosis-inducing ligand (TRAIL), a protective factor against atherosclerosis, membrane omega-3 index and erythrocyte glutathione availability. Hypoxia mediated changes in TRAIL concentrations and redox glutathione capacity (i.e., GSH/GSSG ratio) were greater in ambulatory conditions (+34 ± 6% and +87 ± 31%, respectively) than in bed rest (+17 ± 7% and +2 ± 27% respectively). Hypoxia-induced cardiometabolic risk is blunted by moderate level of physical activity as compared to bed rest. TRAIL and glutathione redox capacity may contribute to the positive interaction between physical activity and hypoxia. Highlights: - Hypoxia and bed rest activate metabolic and inflammatory markers of atherogenesis. - Hypoxia and physical activity activate selected anti-atherogenic pathways. - Hypoxia and physical activity positive interaction involves TRAIL and glutathione.