Nowadays, donkey's and goat's milk consumption has been reevaluated for its potential benefits to human health. For example, in infants with intolerance to cow's milk, donkey's milk represents a good alternative due to its chemical characteristics similar to those of human milk. On the other hand, goat's milk in virtue of its higher content in short chain, medium chain, mono and polyunsaturated fatty acids than that of cow's milk, is more digestible than the bovine counterpart. From an immunological point of view, donkey's milk is able to induce release of inflammatory and anti-inflammatory cytokines from normal human peripheral blood lymphomononuclear cells, thus maintaining a condition of immune homeostasis. Similarly, goat's milk has been shown to trigger innate and adaptive immune responses in an in vitro human system, also inhibiting the endotoxin-induced activation of monocytes. Finally, in these milks the presence of their own microbiota may normalize the human intestinal microbiota with a cascade of protective effects at intestinal mucosal sites, even including triggering of intestinal T regulatory cells. In the light of the above considerations, donkey's and goat's milk should be recommended as a dietary supplement in individuals with inflammatory and allergic conditions, even including elderly people.

Asthma and obesity are two common disorders often associated in children and characterized by an inflammatory status. Growing evidences support a connection between obesity and asthma since weight reduction can improve asthmatic symptoms. In this study, we have enrolled eighty children: 17 non asthmatics and non obese, 19 obese, 28 asthmatics-obese and, 16 asthmatics non-obese, respectively. In all participants, respiratory functional tests and body mass index (BMI) were calculated. Moreover, systemic inflammation of biomarkers such as T helper (h)1-type, Th2-type and T regulatory-type serum cytokines along with major adipokines was determined. Data will show that the association between asthma and obesity leads to a predominant Th1-type response with an increase in pro-inflammatory cytokines. This inflammatory profile in asthmatics-obese children is sustained by elevated serum levels of leptin and visfatin, while adiponectin concentration is rather diminished. Finally, levels of systemic inflammatory biomarkers positively correlate with the increase in BMI values in all population subgroups.

Childhood obesity is characterized by a low-grade inflammation status depending on the multicellular release of cytokines, adipokines, and reactive oxygen species. In particular, the imbalance between anti-inflammatory T regulatory cells and inflammatory T helper 17 cells seems to sustain such a phlogistic condition. Alterations of gut microbiota since childhood also contribute to the maintenance of inflammation. Therefore, besides preventive measures and caloric restrictions, dietary intake of natural products endowed with anti-oxidant and anti-inflammatory activities may represent a valid interventional approach for preventing and/or attenuating the pathological consequences of obesity. In this regard, the use of prebiotics, probiotics, polyphenols, polyunsaturated fatty acids, vitamins, and melatonin in human clinical trials will be described.

There is growing evidence that the prevalence of overweight/obesity is increasing in both developed and developing countries. Furthermore, complications of overweight/obesity occurring during childhood may influence the healthy status in adulthood. On these grounds, here we have enrolled 15 overweight/obese, 15 normal weight and 15 underweight children. A series of parameters, such as eating habits thanks to the Body Mass Index (BMI), Youth Healthy Eating Index (YHEI), activity and inactivity, salivary nitric oxide concentration (NO), were determined and correlated between them. In particular, correlations of BMI with YHEI, activity/inactivity, and correlations of salivary NO concentration with YHEI, BMI and activity/inactivity were evaluated. In overweight and obese subjects, a positive correlation between BMI, YHEI, inactivity and salivary NO concentrations was shown, while an inverse correlation was documented between BMI and activity in overweight/obese group. In normal weight and in underweight children, respectively, a positive correlation between lower BMI, YHEI, salivary NO concentration, and higher physical activity was observed.

The environmental impact as well as malnutrition are responsible for an increased incidence of inflammatory diseases with a consequential loss of immune homeostasis. Therefore, administration of nutraceuticals is aimed at reconstituting the immune balance in terms of the so-called immune nutrition. Among many known nutraceuticals, more recently, donkey's and goat's milks have been used as good alternatives to human and bovine milk in various clinical conditions such as allergy, atopy and inflammatory diseases. In fact, both milks possess immunomodulating capacities and release nitric oxide, a potent vasodilator endowed with anti-atherogenic properties. In this review, emphasis will be placed on the consumption of fermented milk and, in particular, on its ability to modulate the aged immune system, even including the intestinal mucosal immune response in elderly. Therefore, for their specific properties donkey's and goat's milk administration to aged people should be encouraged.

he onset of neurodegenerative diseases has become more frequent than in the past also in relation to inappropriate dietary habits adopted in the western world. Nutraceuticals are currently investigated in order to prevent or retard the outcome of the so-called diet-related diseases, even including neurodegenerative pathologies. Here, we have in vitro studied the ability of fermented grape marc (FGM) from Negroamaro (N) and Koshu (K) Vitis vinifera to modulate the function of human peripheral blood mononuclear cells (PBMCs). Actually, both FGMs were able to increase the release and the intracellular content of inflammatory and anti-inflammatory cytokines, the induction of FoxP3 (a biomarker of T regulatory cells) and reduce the production of Granzyme B from PBMCs. Since these FGM-induced effects tend to polarize the immune response toward an anti-inflammatory pathway, the potential use of FGMs may represent a valid therapeutic measure to mitigating neuroinflammation in pathologies such as Parkinson disease and Alzheimer disease

Pre-, pro-, and symbiotics are endowed with a broad spectrum of beneficial effects when administered to animals and humans. A series of experimental and clinical studies have clearly demonstrated that prebiotics, probiotics, or their combination are very effective in attenuating chronic inflammatory conditions such as inflammatory bowel disease or obesity. In addition, these natural products are able to prevent or arrest tumor development, acting on the intestinal microbiota as well as potentiating the immune response. Aging is characterized by a dramatic reduction of both innate and adaptive immune responses, the so-called immunosenescence. This leads to an increased incidence of infections, autoimmune diseases, and cancer in the elderly. Pre-, pro-, and symbiotic administration has been shown to ameliorate the immune response in aging. In particular, administration of a symbiotic to free-living elderly was able to potentiate the release of interleukin-8, thus increasing neutrophils in the host, perhaps explaining the reduced frequency of winter infections in the elderly

Human ageing is characterized by several abnormalities of both innate and adaptive immune responses, thus leading to an increased frequency of infectious, inflammatory, allergic and autoimmune diseases. In elderly patients, among allergic diseases, asthma is a very common pathological event which complicates the dysfunction of many systems. Among a variety of natural products used to modulate the altered immune response, polyphenols have been shown to exert antiinflammatory activities in both young and aged persons. Here, special emphasis will be given to the the immune-modulating effects of Leucoselect® Phytosome® (a dietary supplement enriched in the flavonoid epigallocatechin) administered to frail elderly patients. Leucoselect® Phytosome® was able to upregulate the T helper (Th)1 response [increase in serum concentrations of interleukin (IL)-2 and interferon-γ]. On the other hand, IL-4 serum levels, as an index of Th2 function, fluctuated within normal ranges. Quite interestingly, in this cohort of frail aged patients from South Italy the balance between inflammation (IL-17) and anti-inflammation (IL-10) was preserved, thus suggesting that the Mediterranean diet might have been involved in the observed effects. In conclusion, these data support the ability of Leucoselect® Phytosome® to induce up-regulation of Th1 responses in frail elderly patients which may be beneficial in those patients affected by chronic allergic disorders.

Both innate and adaptive immunity is involved in the cellular immune response against Mycobacterium tuberculosis (Mtb). Alveolar macrophages (Mθ) actively participate to the engulfment and killing of Mtb, while dendritic cells (DCs) act as antigen presenting cells. Also, neutrophils and natural killer cells protect the host against Mtb. Adaptive immunity is based on the DC-mediated activation of Th1 cells, that produce interferon-γ and enhance the microbicidal activity of Mθ. Moreover, T regulatory (Treg) and Th17 cells seem to play antithetic roles in which the former are able to exert anti-inflammatory functions and the latter contribute to the exacerbation of inflammation. Despite such a defensive armamentarium, Mtb has been shown to escape from the host immunity adopting different strategies. Intradermal vaccination with Bacille Calmette Guerin (BCG) has been replaced by the intranasal route using viral-vectored tuberculosis (TB) vaccines which better boost BCG immunization. Also, Mtb filtrate proteins, mucosal adjuvants and IgA monoclonal antibodies have been experimented in the immunotherapy against TB. Vitamin D has been shown to be protective in the course of TB in view of its receptors present on Mθ and Treg cells. Finally, polyphenols have been demonstrated to restore Mtb mediated depression of Mθ function as well as to directly act on Mtb, thus arresting its growth. From our own studies with red grape polyphenols, it emerges that these compounds may support Th1 responses, especially in elderly patients, also exerting Treg cell-mediated anti-inflammatory activity via IL-10 release. Therefore, polyphenol supplementation may contribute to reinforce anti-Mtb defences and mitigate excessive inflammation.

Polyphenols contained in FGM from Negroamaro (N) and Koshu (K) Vitis vinifera have been shown to exhibit several immunomodulating activities. For instance, mice affected by experimental colitis when administered with K-FGM showed an attenuation of the inflammatory process. In murine asthma, K-FGM reduced IgE production and eosinophil number in bronchial alveolar lavage fluid. In vitro, both N- and K-FGM were able to induce T regulatory cells in terms of Foxp-3 molecule expression and release of interleukin-10. In another set of experiments both N- and K-FGM were able to balance rate of proliferation/apoptosis/necrosis of normal human peripheral lymphocytes, thus indicating the property of these compounds to maintain immune homeostatic mechanisms in the host. On the other hand, N- and K-FGM inhibited human basophil degranulation, thus, confirming our previous results obtained with rat basophilic leukemia cells. Finally, N- and K-FGM also decreased oxidative burst of human polymorphonuclear cells and monocytes.Taken together, these findings imply the potential clinical usefulness of FGM administration in inflammatory/allergic conditions, such as chronic asthma.

Parkinson disease (PD) and Alzheimer disease (AD) are neurodegenerative processes whose frequency is dramatically increasing in the western world. Both diseases share a common pathogenic denominator characterized by an exaggerated activation of the systemic and cerebral immune system, respectively. For instance, lipopolysaccharides in PD and amyloid beta in AD trigger microglia and astrocytes to release reactive oxygen species (ROS) and proinflammatory cytokines. Infiltrating peripheral T cells once activated in the central nervous system also contribute to the neurodegenerative process. Besides innovative biotherapy, nutraceuticals or functional foods are currently investigated for their neuroprotective activities. Especially, vitamin D and polyphenols, seem to be promising therapeutic tools for inhibiting ROS formation and arresting cytokine-mediated neuroinflammation in PD and AD.

Aims: Until now, studies related to the morphometric and morphological variations produced on peripheral blood leukocytes from healthy donors by exposure to 1.8 GHz electromagnetic radiation (EMR) yielded controversial results. The aim of this research work is to increase the statistics regarding the above mentioned variations. Methodology: By using a reverberation chamber, which provides a controlled EMR intensity, 108 samples of human leukocytes from healthy donors were exposed to EMR of different intensities (12±4 V/m, 22±6 V/m, 42±9 V/m and 78±10 V/m) for times ranging from 5 min to 24 h. Sham exposed blood samples of the same donors were considered as controls. Using a computerized morphometric method, microscopic observations of the area size occupied by each cell were conducted; in each case the dimensional measurements were carried out on three different samples (from different donors). Besides, morphological observations were conducted staining smeared blood samples with May-Grünwald-Giemsa. Results: Exposed and sham exposed leukocytes average size was compared using the Statistical GraphPad Prism 5.0 software. In 18% out of 108 cases examined, no effects dependent on EMR have been revealed. On the contrary, statistically significant variations in area of exposed leukocytes in comparison to non exposed cells were observed in 82% out of 108 cases examined. In 68% out of 108 cases an increase in leukocyte areas was demonstrated along with morphological variations of cells; in 14% out of 108 the cases, a decrease in leukocyte areas was observed. Conclusions: Even though this study needs a functional evaluation of leukocytes exposed to EMR, our results suggest that 1.8 GHz EMR is able to produce increase in the leukocyte areas as well as morphological alterations.

The increased incidence of allergic disease seems to rely on many factors. Among them, the association between genetic variations of the immune response and environmental pressure by allergens, infectious agents and pollutants should be taken into consideration. In alternative to conventional treatments with corticosteroids and antihistaminics, nutraceuticals have been shown to act on allergic disease either during allergic sensitisation or on consolidated disease. In this review, special emphasis is placed on the effects of dietary polyphenols on three major allergic diseases, namely atopic eczema, food allergy and asthma. Interference of polyphenols with T-helper 2 activation seems to be the main mechanism of their inhibitory effects on allergy development. Moreover, deficits of T-regulatory cells seem to play a pathogenic role in allergic disease and, therefore, these cells may represent a major target of polyphenol activity.

Regulatory T cells either of thymic derivation or induced peripherally play an important role in the suppression of autoimmune and inflammatory disease. In this review, the classification and function of regulatory T cells will be illustrated in healthy conditions and disease. Furthermore, the modulation of regulatory T cells by various dietary products will be described. Special emphasis will be placed on the role of vitamin A and D metabolites, pre- and probiotics, fatty acids and polyphenols. These natural products are also able to modulate the intestinal microbiota, which in turn shapes the gut immunity, including the induction of regulatory T cells.

Nowadays, people are living much longer than they used to do, however they are not free from ageing. Ageing, an inexorable intrinsic process that affects all cells, tissues, organs and individuals, is a post-maturational process that, due to a diminished homeostasis and increased organism frailty, causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. However, the high incidence of death due to infectious, cardiovascular and cancer diseases underlies a common feature in these pathologies that is represented by dysregulation of both instructive and innate immunity. Several studies show that a low-grade systemic inflammation characterizes ageing and that inflammatory markers are significant predictors of mortality in old humans. This pro-inflammatory status of the elderly underlies biological mechanisms responsible for physical function decline and agerelated diseases such as Alzheimer's disease and atherosclerosis are initiated or worsened by systemic inflammation. Understanding of the ageing process should have a prominent role in new strategies for extending the health old population. Accordingly, as extensively discussed in the review and in the accompanying related papers, investigating ageing pathophysiology, particularly disentangling agerelated low grade inflammation, is likely to provide important clues about how to develop drugs that can slow or delay ageing

Over recent years, neutrophil functions have extensively been reevaluted. For instance, it has been found that extracellular traps generated by activated neutrophils are able to perform a very effective antimicrobial activity against a plethora of microorganisms. In addition, neutrophils possess the ability to interact with monocytes/macrophages either via release of their granule content or via efferocytosis. Efferocytosis is based on neutrophil clearance by macrophages, which, in turn, exert pro- or antinflammatory effects. Furthermore, alarmins released by neutrophils have been shown to mobilize and activate dendritic cells as well as macrophages for antigen-presentation to occur. Finally, other researchers have demonstrated that neutrophils act as suppressor cells by deprivation of arginine in T cells. From a clinical point of view, it is well known that neutrophils are present as activated effector cells in a number of diseases such as infectious disease, sepsis, autoimmune disease, cardiovascular disease and tumors. They play pro-inflammatory and angiogenetic effects in some cases, while in other cases they depress host immune response. In this review, also emphasis will be placed on neutrophil functional deficits which seem to participate to the pathogenesis of various diseases, e.g., viral hepatitis C infection and inflammatory bowel disease. Finally, novel therapeutic measures able to modulate neutrophil functions will be described with special reference to both immune agents and natural products

The continuous antigenic triggering has greatly contributed to the evolution of the immune system and, therefore, animals have developed cells able to cope with a broad variety of microbial antigens and or their toxins, e.g., endotoxins. At the same time, intestinal commensals have evolved along with human progress and introduction of new foods, thus empowering both regional and systemic immune response. In this review, some important steps in the evolution of the immune system will be analyzed such as organization of lymphoid organs, formation of germinal centers, leukocyte attraction to tissue, function of Toll like receptors and role of antimicrobial peptides. In particular, the major phylogenetic acquisitions of living organisms in the assessment of the immune machinery will be emphasized. Finally, fish will be taken into consideration as animal models of human diseases also in view of drug design strategies. Special attention will be focused on vaccinated salmon and zebrafish models

Polyphenols are ubiquitous compounds present in the vegetal kingdom and endowed with an array of beneficial activities to human health. In this review, the effects of dietary polyphenols on the prevention and/or mitigation of cancer, neurodegenerative diseases, obesity, metabolic syndrome and atherosclerosis will be illustrated. Moreover, emphasis will be placed on our own data concerning the in vitro effects performed by polyphenols from an italian red wine "Negroamaro" on human healthy peripheral blood mononuclear cells. Particularly, production of nitric oxide and maintenance of the inflammatory/anti-inflammatory cytokine network will be discussed also in relation to potential application to human age-related diseases. In conclusion, polyphenols in virtue of the plethora of protective effects manifested in various experimental models and clinical trials seem to be appropriate as dietary supplements for preventing the functional decline of organs with age

This editorial overview is aimed at reviewing all the work published by the Journal Endocrine Metabolic Immune Disorders-Drug Targets over the period 2012-2014. The main body of publications has been divided either into a section based on special issues and meeting proceedings or various specific sections according to different types of pathologies related to the field of endocrine metabolic immune disorder-drug targeting

Intestinal microbiota and gut-associated lymphoreticular tissue are in a dynamic equilibrium, the rupture of which causes a condition of dysbiosis in the host. Among many natural foods, milk, because of its composition, is able to influence the host–microbiota relationship. Donkey’s and goat’s milk represents a good alternative to human milk. Healthy effects of both kinds of milk have been reported in either in vitro or in vivo experiments. When administered to elderly subjects, donkey’s milk increased the release of interleukins 6 and 8, while goat’s milk exerted opposite effects. With special reference to fermented cow’s milk, a symbiotic (Gorbach and Goldin) when administered to another group of elderly people, behaved as donkey’s milk upregulating interleukins 6, 8 and also 1. In conclusion, the ability of milk and fermented milk to modulate the altered immune response in senescence needs to be exploited more for maintaining healthy aging.

Endothelial cells (ECs) express on their membrane Toll like receptor (TLR)-4 and, therefore, are able to interact with lipopolysaccharides (LPS) or endotoxins, major constituents of the Gram-negative bacteria outer membrane. The impact of LPS on ECs can be either direct or mediated via release of cytokines and/or chemokines originated from monocytes/macrophages. In this review, the effect of the interaction between LPS and ECs on the outcome of various human diseases such as preeclampsia, hereditary haemorrhagic teleangiectasia, atherosclerosis and sepsis will be illustrated. Finally, the major therapeutic attempts aimed at neutralizing LPS and, therefore, their influence on ECs will be discussed

Intestinal microbiota and gut immune systems interact each other, maintaining a condition of homeostasis in the context of the intestinal habitat. However, both systems undergo modifications in elderly, thus accounting for a low grade inflammatory status which, in turn, may evolve toward more severe pathological conditions such as inflammatory bowel disease and colon rectal cancer. In addition, in western societies dietary habits may negatively influence the microbiota composition, also altering gut immune response which is per se impaired in elderly. In order to prevent the outcome of aged-related disease, supplementation of nutraceuticals able to correct abnormalities of both immune system and microbiota has become more frequent than in the past. In this respect, a better identification of components of the aged microbiota as well as a deeper analysis of gut mucosal immunity function should be pursued

The innate lymphoid cells (ILCs) have been grouped into three main categories: ILC1s [T helper (h)1-like cells], ILC2s (Th2-like cells) and ILC3s (Th17-like cells), respectively. In particular, ILC3s are responsible for the secretion of both interleukin (IL)-17 and IL-22, which play either protective (antimicrobial and repairing activities) or harmful (inflammation and tumor growth) roles into the host. Here, some putative interventional studies will be hypothesized, taking into account that activation of innate cell receptors, arylhydrocarbon receptor and gut microbiota, respectively, contribute to both differentiation and function of ILC3s. A series of biological and natural compounds may represent putative regulators of these cells in the gut. In this respect, the modulating effects of agonist and antagonists of Toll-like receptors and nucleotide binding oligomerization domain-like receptors, polyphenols and probiotics will be described in detail.

Gut immune system is daily exposed to a plethora of antigens contained in the environment as well as in food. Both secondary lymphoid tissue, such as Peyer's patches, and lymphoid follicles (tertiary lymphoid tissue) are able to respond to antigenic stimuli releasing cytokines or producing antibodies (secretory IgA). Intestinal epithelial cells are in close cooperation with intraepithelial lymphocytes and possess Toll-like receptors on their surface and Nod-like receptors (NLRs) which sense pathogens or pathogen-associated molecular patterns. Intestinal microbiota, mainly composed of Bacteroidetes and Firmicutes, generates tolerogenic response acting on gut dendritic cells and inhibiting the T helper (h)-17 cell anti-inflammatory pathway. This is the case of Bacteroides fragilis which leads to the production of interleukin-10, an anti-inflammatory cytokine, from both T regulatory cells and lamina propria macrophages. Conversely, segmented filamentous bacteria rather induce Th17 cells, thus promoting intestinal inflammation. Intestinal microbiota and its toxic components have been shown to act on both Nod1 and Nod2 receptors and their defective signaling accounts for the development of inflammatory bowel disease (IBD). In IBD a loss of normal tolerance to intestinal microbiota seems to be the main trigger of mucosal damage. In addition, intestinal microbiota thanks to its regulatory function of gut immune response can prevent or retard neoplastic growth. In fact, chronic exposure to environmental microorganisms seems to be associated with low frequency of cancer risk. Major nutraceuticals or functional foods employed in the modulation of intestinal microbiota are represented by prebiotics, probiotics, polyunsaturated fatty acids, amino acids and polyphenols. The cellular and molecular effects performed by these natural products in terms of modulation of the intestinal microbiota and mostly attenuation of the inflammatory pathway are described.