Search

Background Despite the evidence that plants do not possess sessile cells, they are able to mount a vigorous immune response against invaders or under stressful conditions. Mechanisms of action: Plants are endowed with pattern recognition receptors (PPRs) which perceive damage-associated molecular patterns and microbe-associated molecular patterns or pathogen-associated molecular patterns (PAMPs), respectively. PPR activation leads to either the initiation of PAMP-triggered immunity (PTI) (early response) or the effectortriggered immunity (ETI). Both PTI and ETI contribute to plant systemic acquired resistance as also an expression of immunological memory or trained immunity. Plant immune receptors: PTI is initiated by activation of both receptor-like kinases and receptor-like proteins, while ETI depends on nucleotide-binding leucine-rich-repeat protein receptors for microbe recognition. Peptides involved in plant defenses: Plant chloroplasts contribute to both PTI and ETI through production of peptides which act as hormones or phytocytokines. Salicylic acid, jasmonic acid and ethylene are the major compounds involved in plant defense. Specific aims The interaction between plant receptors and/or their products and bacterial components will be discussed. Also emphasis will be placed on plant microbiome for its contribution to plant immune response. Finally, the mutual interplay between insects and plants will also be illustrated. Conclusion A better knowledge on plant immunity may pave the way for the exploitation of plant derivatives in the field of agriculture and medicine, as well.

Background and objectives Dietary habits strongly influence our health status, mostly, in terms of maintenance of the inflammatory/anti-inflammatory homeostasis. High fat and high sugar diets account for the development of a low-grade inflammation which is the pathogenic common denominator of various chronic disease. Severe Acute Respiratory Syndrome Coronavirus (SARS)-CoV2 (COVID-19) infection affects all ages and especially frail elderly people and a nutri-tional intervention seems to be crucial in the course of this pandemic. The present review describes the properties of some vegetal products and their derivatives, such as Lupin sp., garlic, salvia and extra virgin olive oil (EVOO) that can be exploit-ed for their beneficial effects, as preventive and/or nutritional treatment of coronavirus disease SARS-CoV2. Discussion Lupin, salvia, garlic and EVOO share overlapping properties, such as anti-oxidant, anti-inflammatory and anti-viral activities. Quite importantly, these products and their derivatives are able to recover the expression of angiotensin con-verting enzyme expression 2 on cell membrane, otherwise suppressed by COVID-19 binding and entry into cytoplasm. Conclusion Dietary administration of the above nutraceuticals or their extracts may play a preventive or nutritional role in the course of SARS-CoV2 infection, even including the effects of the lockdown and the condition of inflamm-ageing.

Background: Our previous findings demonstrated that in vitro supplementation of polyphenols, extracted from seeds of red grape (Nero di Troia cultivar), to peripheral lymphomonocytes from patients affected by allergic contact dermatitis (ACD) to nickel (Ni) could reduce the release of proinflammatory cytokines and nitric oxide (NO), while increasing the levels of interleukin (IL)-10, an anti-inflammatory cytokine. Objective: To assess whether an intervention with oral administration of polyphenols leads to a reduction of peripheral biomarkers in ACD patients. Methods: At T0, 25 patients affected by ACD to Ni were orally administered with 300 mg polyphenols prodie extracted from seeds of red grape (Nero di Troia cultivar) (NATUR-OX®) for 3 months (T1). The other 25 patients affected by ACD to Ni received placebo only for the same period of time. Serum biomarkers were analyzed at T0 and T1. In both groups, seven dropouts were recorded. Result: At T1 in comparison to T0, in treated patients, values of interferon-γ, IL-4, IL-17, pentraxin 3 and NO decreased, while IL-10 levels increased when compared with T0 values. Conversely, in placebo- treated patients, no modifications of biomarkers were evaluated at T1. Conclusion: Present laboratory data rely on the anti-oxidant, anti-inflammatory and anti-allergic properties of polyphenols.

Background & Objectives: In old people, both innate and adaptive immune responses are impaired, thus leading to a condition of systemic inflamm-ageing, even including the involvement of the central nervous system (CNS). Aims: Here, main mechanisms of the immune ageing and neuro-inflammation will be discussed along with the dietary approaches for the modulation of age related diseases. Discussion: Neuroinflammation is caused by the passage of inflammatory mediators through the brain blood barrier to CNS. Then, in the brain, antigenic stimulation of microglia and/or its activation by peripheral cytokines lead to a robust production of free radicals with another wave of proinflammatory cytokines which, in turn, causes massive neuronal damage. Also, infiltrating T cells [T helper (h) and T cytotoxic cells] contribute to neuronal damage. Additionally, a peripheral imbalance between inflammatory Th17 cells and anti-inflammatory T regulatory cells seems to be prevalent in the aged brain, thus leading to a proinflammatory profile. Alzheimer’s disease, Parkinson’s disease and multiple sclerosis will be described as typical neurodegenerative diseases. Finally, modulation of the immune response thanks to the anti-oxidant and anti-inflammatory effects exerted by dietary products and nutraceuticals in ageing will be discussed. Special emphasis will be placed on polyunsaturated fatty acids, polyphenols, micronutrients and pre-probiotics and synbiotics. Conclusion: Ageing is characterized by an imbalance subversion of the immune system with a condition of inflamm-ageing. Neuroinflammation and neurodegenerative diseases seem to be a central manifestation of a peripheral perturbation of the immune machinery. Dietary products and nutraceuticals may lead to a down-regulation of the oxidative and pro-inflammatory profile in ageing.

Background: Heavy metals [arsenic, aluminium, cadmium, chromium, cobalt, lead, nickel (Ni), palladium and titanium] are environmental contaminants able to impact with host human cells, thus, leading to severe damage. Objective: In this review, the detrimental effects of several heavy metals on human organs will be discussed and special emphasis will be placed on Ni. In particular, Ni is able to interact with Toll-like receptor-4 on immune and non-immune cells, thus, triggering the cascade of pro-inflammatory cytokines. Then, inflammatory and allergic reactions mediated by Ni will be illustrated within different organs, even including the central nervous system, airways and the gastrointestinal system. Discussion: Different therapeutic strategies have been adopted to mitigate Ni-induced inflammatoryallergic reactions. In this context, the ability of polyphenols to counteract the inflammatory pathway induced by Ni on peripheral blood leukocytes from Ni-sensitized patients will be outlined. In particular, polyphenols are able to decrease serum levels of interleukin (IL)-17, while increasing levels of IL- 10. These data suggest that the equilibrium between T regulatory cells and T helper 17 cells is recovered with IL-10 acting as an anti-inflammatory cytokine. In the same context, polyphenols reduced elevated serum levels of nitric oxide, thus, expressing their anti-oxidant potential. Finally, the carcinogenic potential of heavy metals, even including Ni, will be highlighted. Conclusion: Heavy metals, particularly Ni, are spread in the environment. Nutritional approaches seem to represent a novel option in the treatment of Ni-induced damage and, among them, polyphenols should be taken into consideration for their anti-oxidant and anti-inflammatory activities.

Background: The relationship between atopic dermatitis and allergic contact dermatitis is frequently debated, particularly in children. The impaired skin barrier of atopic subjects can facilitate the penetration of exogenous agents and its mutations in the filaggrin gene might be implicated in an increased risk to develop contact dermatitis. Moreover, atopic children are protractedly exposed to chemical substances contained in skin care products from an early age. Patients And Methods: The aim of this retrospective study is to determine if atopic children are more prone to allergic contact dermatitis and which substances are more frequently related to this disease. From 2014 to 2016, a total of 268 children under 14 years with a history of eczematous dermatitis, of whom 141 (52.6%) were affected, and 127 (47.4%) were not affected by AD, underwent patch testing with the baseline S.I.D.A.P.A standard series. Results: Based on the results of our study, the prevalence of contact allergy in atopic children is comparable to that noted in non-atopic children. The most frequent causes of contact allergy in children are fragrances, and their prevalence is significantly higher in atopic children (19.9%) than in non-atopic ones, (11.8%; p < .05). Conclusion: Our study highlights the importance of patch testing in atopic children for continuously monitoring the trends and changes of contact allergies that are a common disease and is even significantly increasing for some allergens, as fragrances. We may speculate that the protracted use of skincare products, associated with the impaired skin barrier of atopic children, enhances the risk of sensitization to the ingredients of these products.

Background and Objective: Hepatopancreas is an accessory organ associated with the liver in some fish, even including sea bass (Dicentrharcus labrax L.). Hepatopancreas contains an exocrine portion but until now its function has poorly been investigated. Methods: Here, European farmed sea bass have been treated with a feed enriched in polyphenols extracted from seeds of red grape (Nero di Troia cultivar) at two different doses (100 and 200 mg/kg, respectively) from day 273 to day 323. In fish samples, hepatopancreas area sizes have been measured to evaluate the effects of this dietary regimen on its morphology. Results: Quite interestingly, in treated fish area sizes of hepatopancreas were higher than those detected in untreated fish. Two hundred mg dose of polyphenols was more effective than that of 100 mg/kg polyphenols. Finally, hepatic polyphenol concentration was diminished in fish receiving 100 mg dose polyphenols and normalized with 200 mg dose in comparison to untreated fish. This evidence suggests the utilization of polyphenols for liver function, even including hepatopancreas development. Conclusion: Our data suggest an expansion of hepatopancreas induced by polyphenol administration that is also associated with less mortality in farmed fish.

Background:Sepsis is a clinical condition due to an infectious event which leads to an early hyper-inflammatory phase followed by a status of tolerance or immune paralysis. Hyper-inflammation derives from a massive activation of immune (neutrophils, monocytes/macrophages, dendritic cells and lymphocytes) and non-immune cells (platelets and endothelial cells) in response to Gram-negative and Gram-positive bacteria and fungi.Discussion:A storm of pro-inflammatory cytokines and reactive oxygen species accounts for the systemic inflammatory response syndrome. In this phase, bacterial clearance may be associated with a severe organ failure development. Tolerance or compensatory anti-inflammatory response syndrome (CARS) depends on the production of anti-inflammatory mediators, such as interleukin-10, secreted by T regulatory cells. However, once triggered, CARS, if prolonged, may also be detrimental to the host, thus reducing bacterial clearance.Conclusion:In this review, the description of pathogenic mechanisms of sepsis is propaedeutic to the illustration of novel therapeutic attempts for the prevention or attenuation of experimental sepsis as well as of clinical trials. In this direction, inhibitors of NF-κB pathway, cell therapy and use of dietary products in sepsis will be described in detail.

Background: Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) (COVID-19) infection provokes serious clinical consequences, which in many situations need hospitalization of the patient in Intensive Care Unit. Additionally, SARS-COV-2 infection can indirectly cause deaths in aged individuals as well as in patients with comorbidities. Objective: To evaluate the effects of nutrition during the COVID-19 pandemic in both hospitalized patients and in the general population. Methods: Authors searched Medline (PubMed), Web of Science, EMBASE, Cochrane Library, Google, and Institutional websites for medical subheadings terms and free full text referred to “SARS-CoV-2”, COVID-19”, “nutrition”, “immune system”, before 31st July 2020. Results: A total of 20 articles describing different nutritional interventions for patients with SARS-CoV-2 infection focusing on the general population have been included. Of these, 6 studies are dealing with nutritional interventions for patients with SARS-CoV2 infection and the others are focalized on a potential beneficial effect exerted by a Mediterranean-type diet, related to the supplementation of micronutrients and vitamins. Conclusion: A correct lifestyle even including the consumption of nutrient largely present in MD, may be beneficial for preventing or improving prognosis in the SARS-CoV-2 infection.

Objective: Obesity induced by high-fat diet (HFD) elicits white adipose tissue dysfunction. In this study, we have hypothesized that the metabolic modulator eicosapentaenoic acid (EPA) combined with the antioxidant hydroxytyrosol (HT) attenuates HFD-induced white adipose tissue (WAT) alterations. Methods: C57BL/6J mice were administered with a HFD (60% fat, 20% protein, 20% carbohydrates) or control diet (CD, 10% fat, 20% protein, 70% carbohydrates), with or without EPA (50 mg/kg/day), HT (5 mg/kg/day), or both for 12 weeks. Determinations in WAT include morphological parameters, EPA and docosahexaenoic acid content in phospholipids (gas chromatography), lipogenesis, oxidative stress (OS) and inflammation markers, and gene expression and activities of transcription factors, such as sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor-gamma (PPAR-&gamma, ), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-&kappa, B) (p65 subunit) and nuclear factor erythroid 2-related factor 2 (Nrf2) (quantitative polymerase chain reaction and enzyme linked immunosorbent assay). Results: HFD led to WAT hypertrophy in relation to PPAR-&gamma, downregulation. WAT metabolic dysfunction was characterized by upregulation of lipogenic SREBP-1c system, mitochondrial energy metabolism depression, loss of the antioxidant Nrf2 signaling with OS enhancement, n-3 long-chain polyunsaturated fatty acids depletion and activation of the pro-inflammatory NF-&kappa, B system. EPA and HT co-supplementation diminished HFD-dependent effects additively, reaching values close or similar to controls. Conclusion: Data presented strengthen the importance of combined protocols such as EPA plus HT to attenuate metabolic-inflammatory states triggered by obesity.

Over the past 20 years, Endocrine Metabolic Immune Disorders-Drug Targets (EMIDDT) journal has been covering a broad field of intertwined topics related to pathogenesis, diagnosis, and therapy of endocrine, metabolic, and immune diseases. At first, the journal publications were restricted to reviews only and, then, original article submissions have also been accepted. EMIDDT represents as a successful journal in continuous expansion with 10 issues in 2020 and a current impact factor (IF) equal to 1.973. Moreover, since 2019, EMIDDT is the official journal of the Italian AME (Associazione Medici Endocrinologi), also linked to the American Association of Endocrinologists. Such a connection has given more impetus to the journal in terms of additional higher-quality submissions. In order to celebrate the 20th anniversary of EMIDDT, the content of some original representative articles published by the journal in the past and current years will be illustrated with special emphasis on cellular and molecular bases of drug targeting.

Background: Plants have represented an essential source of foods for human beings, as confirmed by archeological studies that have revealed on old pottery the presence of proteins from cereal and legumes. Specific aims: In this review, major healthy effects derived from the consumption of plant fibers, polyunsaturated fatty acids (PUFAs) and polyphenols, respectively, will be described with special emphasis on their mechanisms of action, both at cellular and molecular levels. Dietary compounds: Fibers exhibit a prevalent prebiotic effect, acting on the intestinal microbiota with the production of protective metabolites, such as short chain fatty acids. Plant PUFAs include α-linolenic and stearidonic acids, which are precursors of other two major PUFAs, namely, eicosapentaenoic and docosahexaenoic acids. Some clinical trials demonstrated the ability of PUFAs to lower the risk of coronary disease, while other trials did not confirm such a finding. Polyphenols are endowed with anti-oxidant and anti-inflammatory activity in view of their property to inhibit NF-κB activation, to induce the anti-inflammatory T regulatory cells and to normalize the intestinal microbiota. The beneficial effects of polyphenols on obesity/diabetes, allergic/autoimmune and inflammatory disease are elucidated. Conclusion: Plants are one of the major sources of healthy dietary products, whose exploitation may promote prevention of chronic disease.

Platelets are cellular fragments derived from bone-marrow megacaryocytes and they are mostly involved in the haemostasis and coagulation. However, according to recent data, platelets are able to perform novel immune functions. In fact, they possess a receptorial armamentarium on their membrane for interacting with innate and adaptive immune cells. In addition, platelets also secrete granules which contain cytokines and chemokines for activating and recruiting even distant immune cells. The participation of platelets in inflammatory processes will also be discussed in view of their dual role in terms of triggering or resolving inflammation. Involvement of platelets in disease will be illustrated, pointing to their versatile function to either up- or down-regulate pathological mechanisms. Finally, despite the availability of some anti-platelet agents, such as aspirin, dietary manipulation of platelet function is currently investigated. In this regard, special emphasis will be placed on dietary omega-3 polyunsaturated fatty acids (PUFAs) and polyphenol effects on platelets. Platelets play a dual role in inflammatory-immune-mediated diseases either activating or deactivating immune cells. Diet based on substances, such as omega-3 PUFAs and polyphenols, may act as a modulator of platelet function, even if more clinical trials are needed to corroborate such a contention.

In this review, special emphasis will be placed on red grape polyphenols for their anti-oxidant and anti-inflammatory activities. Therefore, their capacity to inhibit major pathways responsible for activation of oxidative systems and expression and release of pro-inflammatory cytokines and chemokines will be discussed. Furthermore, regulation of immune cells by polyphenols will be illustrated with special reference to the activation of T regulatory cells which support a tolerogenic pathway at intestinal level. Furthermore, the effects of red grape polyphenols will be analyzed in obesity, as a low grade systemic inflammation. Also, possible modifications of inflammatory bowel disease biomarkers and clinical course have been studied upon polyphenol administration, either in animal models or in clinical trials. Moreover, the ability of polyphenols to cross the blood-brain barrier has been exploited to investigate their neuroprotective properties. In cancer, polyphenols seem to exert several beneficial effects, even if conflicting data are reported about their influence on T regulatory cells. Finally, the effects of polyphenols have been evaluated in experimental models of allergy and autoimmune diseases. Conclusively, red grape polyphenols are endowed with a great anti-oxidant and anti-inflammatory potential but some issues, such as polyphenol bioavailability, activity of metabolites and interaction with microbiota, deserve deeper studies.

Antimicrobial peptides (AMPs) are phylogenetically ancient substances released by living organisms for self protection against a broad variety of microbes. Moreover, AMPs are endowed with immune modulatory activities, linking innate and adaptive immunity together. Lantibiotics are AMPs of bacterial origin currently investigated for the generation of a new class of anti-infective compounds, owing to the phenomenon of antibiotic resistance against a broad variety of bacteria. Also, plants and marine AMPs are screened as novel drugs against human pathogens. Human AMPs encompass defensins and cathelicidins produced by various cell types mostly at mucosal sites. Besides their antimicrobial activity, both AMPs have been shown to trigger either inflammatory or anti-inflammatory pathways. Food-derived AMPs are mostly represented by lactoferrin and lysozyme both present in secretions, e.g., milk, and appear to be very exploitable for the generation of functional foods. Finally, the role of natural products ingested with food or administered as supplements on induction and production of AMPs will be discussed.

BACKGROUND Allergy to Anisakis simplex (s.) is spreading due to the increased consumption of raw, smoked or marinated fish. In man, Anisakis s. can directly attack the gastrointestinal mucosa, provoking a parasitosis known as anisakiasis, or giving rise to the formation of IgE and, finally, inducing IgE-mediated reactions like urticaria, angioedema and anaphylactic shock. During recent years, a dietary approach to Anisakis s. infestation has also been addressed. METHODS A total of 620 patients with urticaria, angioedema, or both and a history of anaphylaxis following consumption of raw, smoked or marinated fish were recruited, evaluated for specific IgE levels to Anisakis s. and subjected to Skin Prick test. Following 18 month fish-free diet, patients were reevaluated at 6, 12 and 18 months, respectively. Patients undergoing diet were selected among those who had a clinical history with multiple accesses to first aid. RESULTS After 6-month fish-free diet, we recorded an improvement of symptoms and a remarkable reduction of specific IgE levels. The extension of the diet over 6 months in some cases resulted in a further reduction of specific IgE levels. CONCLUSION Data obtained confirm the importance of a fish-free diet in patients with severe symptoms since a new antigenic exposure coincides with a relapse of symptoms and increased IgE levels. This last point should be kept in mind and carefully evaluated in patients at risk for anaphylaxis or angioedema.

Background: Olive tree leaves have been used in the Mediterranean area as traditional medicine in virtue of their healthy effects. Olive leaf extracts (OLEs) contain higher amounts of polyphenols than those detected in the extra virgin olive oil and fruit. Several lines of evidence support the cardioprotective, anti-oxidant and anti-inflammatory activities exerted by OLEs. Methods: Peripheral blood mononuclear cells from twenty-five healthy donors were cultured in the presence of 3 µg of two OLE extracts, extract A (resuspended in water) and extract B (resuspended in 70% ethanol). After harvesting, cell pellets were used for cytofluorimetric phenotyping, while supernatants were assayed for cytokine release by means of ELISA. Furthermore, in the same supernatants nitric oxide (NO) content was determined. Results: Both extracts, but especially extract A, increased absolute numbers of CD8+ and natural killer (NK) cells. In addition, an increased production of interferon (IFN)-γ by both extracts as an expression of T helper (h)1 activation was observed. Finally, both extracts enhanced NO release. Conclusion: OLEs, and mostly extract A, are able to in vitro modify healthy human immune response by increasing IFN-γ production which seems to be associated to the higher absolute numbers of CD8+ and NK cells and this may suggest a reinforcement of the anti-tumor activity. Furthermore, increased levels of NO may indicate the potential cardioprotective effects exerted by OLEs in virtue of their vasodilation dependent activity. Finally, OLEs are able to maintain the equilibrium between T regulatory cells and Th17 cells as evidenced by unmodified levels of interleukin (IL)-IL-10 and IL-17, respectively. In the light of these results, OLEs are potential therapeutic compounds for the treatment of chronic inflammatory disease, also preventing cardiovascular event outcome.

Tumors are complex tissues in which transformed cells communicate with the surrounding microenvironment and evolve traits promoting their own survival and malignancy. Hypoxia and inflammation are constant characteristics of prostate tumor microenvironment influencing both cancer stem cells and differentiated tumor cells. HIFs and NF-kB are the key regulators of the transcriptional response to hypoxic and inflammatory stresses, respectively, and a crosstalk between HIFs and NF-kB pathways has been widely documented. Similarly, androgen and estrogen signaling, that play important roles in the growth and function of normal prostate gland, when deregulated, have a significant part in the acquisition of hallmarks of malignant diseases. Moreover, androgen and estrogen receptors have been shown to intersect with the HIF/NF-kB signaling in prostate cancer. Aim of this review is to present the current knowledge regarding the crucial role, in prostate cancer progression, of a molecular network linking hypoxia, pro-inflammatory response and steroid receptors.

The in vitro ability of polyphenols, extracted from red grape, to modulate peripheral blood mononuclear cell responses has been evaluated in 20 obese (Ob) people. With regard to cytokine release in response to phorbol myristate acetate (PMA), levels of interleukin-2 (IL-2), interferon-γ(IFN-γ), IL-4, IL-10, and IL-17 were higher in the Ob than in healthy (H) subjects.Vice versa, IL-21 concentrations were detected only in H people but they were undetectable in the Ob counterpart. In general terms, levels of IL-1β, IL-6, IL-8, and tumor necrosis factor-αwere higher in Ob people when compared to H controls. On the other hand, polyphenols did not modify IFN-γ, IL-4, and IL-17 levels. However, an increase in IL-2 was observed in H individuals, whereas its levels were decreased in the Ob counterpart. Polyphenols significantly increased IL-10 release from H donors, whereas a trend to increase was observed in Ob people. In addition, polyphenols were able to significantly increase levels of H IL-21, while this was not the case in Ob people. Since IL-21 is an inducer of Th17 cells, it is likely that polyphenols may suppress the sources of this cytokineviaproduction of IL-10. Accordingly, polyphenols decreased IL-1βand IL-6 release in comparison to H controls.

Background: Eosinophils are primitive myeloid cells derived from bonemarrow precursors and require the intervention of interleukin (IL)-5 for their survival and persistence in blood and tissues. Under steady-state conditions, they contribute to immune regulation and homeostasis. Under pathological circumstances, eosinophils are involved in host protection against parasites and participate in allergy and inflammation. Discussion: Mostly, in asthma, eosinophils provoke airway damage via the release of granule contents and IL-13 with mucus hypersecretion and differentiation of goblet cells. Then, tissue remodeling follows with the secretion of transforming growth factor-β. Eosinophils are able to kill helminth larvae acting as antigen-presenting cells with the involvement of T helper (h)-2 cells and subsequent antibody response. However, they also exert pro-worm activity with the production of suppressive cytokine (IL- 10 and IL-4) and inhibition of nitric oxide. Eosinophils may play a pathogenic role in the course of chronic and autoimmune disease, e.g., inflammatory bowel disease and eosinophilic gastroenteritis, regulating Th2 responses and promoting a profibrotic effect. In atopic dermatitis, eosinophils are commonly detected and may be associated with disease severity. In cutaneous spontaneous urticaria, eosinophils participate in the formation of wheals, tissue remodeling and modifications of vascular permeability. With regard to tumor growth, it seems that IgE can exert anti-neoplastic surveillance via mast cell and eosinophil-mediated cytotoxicity, the so-called allergo-oncology. From a therapeutic point of view, monoclonal antibodies directed against IL-5 or the IL-5 receptors have been shown to be very effective in patients with severe asthma. Finally, as an alternative treatment, polyphenols for their anti-inflammatory and anti-allergic activities seem to be effective in reducing serum IgE and eosinophil count in bronchoalveolar lavage in murine asthma. Conclusion: Eosinophils are cells endowed with multiple functions and their modulation with monoclonal antibodies and nutraceuticals may be effective in the treatment of chronic disease.

Mast cells (MCs) have recently been re-interpreted in the context of the immune scenario in the sense that their pro-allergic role is no longer exclusive. In fact, MCs even in steady state conditions maintain homeostatic functions, producing mediators and intensively cross-talking with other immune cells. Here, emphasis will be placed on the array of receptors expressed by MCs and the variety of cytokines they produce. Then, the bulk of data discussed will provide readers with a wealth of information on the dual ability of MCs not only to defend but also to offend the host. This double attitude of MCs relies on many variables, such as their subsets, tissues of residency and type of stimuli ranging from microbes to allergens and food antigens. Finally, the relationship between MCs with basophils and eosinophils will be discussed.

Mast cells (MCs) bear many receptors which allow them to respond tAs far as treatment of MC-derived diseases is concerned, allergen immunotherapy as well as other attempts to reduce MC-activation will be outlined according to the recent data. Finally, in agreement with current literature and our own data polyphenols have been demonstrated to attenuate type I allergic reactions and contact dermatitis in response to nickel. The use of polyphenols in these diseases will be discussed also in view of MC involvement.o a variety of exogenous and endogenous stimuli. However, MC function is dual since they can initiate pathological events or protect the host against infectious challenges.:The role of MCs in disease will be analyzed in a broad sense, describing cellular and molecular mechanisms related to their involvement in auto-inflammatory diseases, asthma, autoimmune diseases and cancer. On the other hand, their protective role in the course of bacterial, fungal and parasitic infections will also be illustrated.:Mast cells (MCs) bear many receptors that allow them to respond to a variety of exogenous and endogenous stimuli. However, MC function is dual since they can initiate pathological events or protect the host against infectious challenges.

In this study the mechanisms are explored, which modulate expression and function of cell surface adhesive glycoproteins of the Immunoglobulin Supergene Family (IgSF), and in particular of its Contactin subset, during neuronal precursor developmental events. In this context, a specific topic concerns the significance of the expression profile of such molecules and their ability to modulate signaling pathways activated through nutraceuticals, in particular polyphenols, administration. Both in vitro and in vivo approaches are chosen. As for the former, by using as a model the human SH-SY5Y neuroblastoma line, the effects of grape seed polyphenols are evaluated on proliferation and commitment/differentiation events along the neuronal lineage. In SH-SY5Y cell cultures, polyphenols were found to counteract precursor proliferation while promoting their differentiation, as deduced by studying their developmental parameters through the expression of cell cycle and neuronal commitment/differentiation markers as well as by measuring neurite growth. In such cultures, Cyclin E expression and BrdU incorporation were downregulated, indicating reduced precursor proliferation while increased neuronal differentiation was inferred from upregulation of cell cycle exit (p27-Kip) and neuronal commitment (NeuN) markers as well as by measuring neurite length through morphometric analysis. The polyphenol effects on developmental parameters were also explored in vivo, in cerebellar cortex, by using as a model the TAG/F3 transgenic line, which undergoes delayed neural development as a consequence of Contactin1 adhesive glycoprotein upregulation and premature expression under control of the Contactin2 gene (Cntn-2) promoter. In this transgenic line, a Notch pathway activation is known to occur and polyphenol treatment was found to counteract such an effect, demonstrated through downregulation of the Hes-1 transcription factor. Polyphenols also downregulated the expression of adhesive glycoproteins of the Contactin family themselves, demonstrated for both Contactin1 and Contactin2, indicating the involvement of changes in the expression of the underlying genes in the observed phenotype. These data support the hypothesis that the complex control exerted by polyphenols on neural development involves modulation of expression and function of the genes encoding cell adhesion molecules of the Contactin family and of the associated signaling pathways, indicating potential mechanisms whereby such compounds may control neurogenesis.

Background: In mice, postnatal immune development has previously been investigated, and evidence of a delayed maturation of the adaptive immune response has been detected. Methods: In this study, the effects of red grape polyphenol oral administration on the murine immune response were explored using pregnant mice (TAG/F3 transgenic and wild type (wt) mice) as the animal model. The study was performed during pregnancy as well as during lactation until postnatal day 8. Suckling pups from polyphenol-administered dams as well as day 30 post-weaning pups (dietary-administered with polyphenols) were used. Polyphenol effects were evaluated, measuring splenic cytokine secretion. Results: Phorbol myristate acetate-activated splenocytes underwent the highest cytokine production at day 30 in both wt and TAG/F3 mice. In the latter, release of interferon (IFN)-&gamma, and tumor necrosis factor (TNF)-&alpha, was found to be higher than in the wt counterpart. In this context, polyphenols exerted modulating activities on day 30 TAG/F3 mice, inducing release of interleukin (IL)-10 in hetero mice while abrogating release of IL-2, IFN-&gamma, TNF-&alpha, IL-6, and IL-4 in homo and hetero mice. Conclusion: Polyphenols are able to prevent the development of an inflammatory/allergic profile in postnatal TAG/F3 mice.

Fish despite their low collocation in the vertebrate phylum possess a complete immune system. In teleost fish both innate and adaptive immune responses have been described with melanomacrophage centers (MMCs) equivalent to mammalian germinal centers. Primary lymphoid organs are represented by the thymus and kidney, while spleen and mucosa-associated lymphoid tissues act as secondary lymphoid organs. Functions of either innate immune cells (e.g., macrophages and dendritic cells) or adaptive immune cells (T and B lymphocytes) will be described in detail, even including their products, such as cytokines and antibodies. In spite of a robust immune arsenal, fish are very much exposed to infectious agents (marine bacteria, parasites, fungi, and viruses) and, consequentially, mortality is very much enhanced especially in farmed fish. In fact, in aquaculture stressful events (overcrowding), microbial infections very frequently lead to a high rate of mortality. With the aim to reduce mortality of farmed fish through the reinforcement of their immune status the current trend is to administer natural products together with the conventional feed. Then, in the second part of the present review emphasis will be placed on a series of products, such as prebiotics, probiotics and synbiotics, β-glucans, vitamins, fatty acids and polyphenols all used to feed farmed fish. With special reference to polyphenols, results of our group using red grape extracts to feed farmed European sea bass will be illustrated. In particular, determination of cytokine production at intestinal and splenic levels, areas of MMCs and development of hepatopancreas will represent the main biomarkers considered. All together, our own data and those of current literature suggests that natural product administration to farmed fish for their beneficial effects may, in part, solve the problem of fish mortality in aquaculture, enhancing their immune responses.

Hepatopancreas is an accessory organ associated with the liver in some fish, even including sea bass (Dicentrharcus labrax L.). Hepatopancreas contains an exocrine portion but until now its function has poorly been investigated.Here, European farmed sea bass have been treated with a feed enriched in polyphenols extracted from seeds of red grape (Nero di Troia cultivar) at two different doses (100 and 200 mg/kg, respectively) from day 273 to day 323. In fish samples, hepatopancreas area sizes have been measured to evaluate the effects of this dietary regimen on its morphology.Quite interestingly, in treated fish area sizes of hepatopancreas were higher than those detected in untreated fish. Two hundred mg dose of polyphenols was more effective than that of 100 mg/kg polyphenols. Finally, hepatic polyphenol concentration was diminished in fish receiving 100 mg dose polyphenols and normalized with 200 mg dose in comparison to untreated fish. This evidence suggests the utilization of polyphenols for liver function, even including hepatopancreas development.Our data suggest an expansion of hepatopancreas induced by polyphenol administration that is also associated with less mortality in farmed fish.

Background: T cell tolerance both at thymic and peripheral levels is a mechanism of protection finalized to eradicate autoreactive T cell clones and/or to maintain immune homeostasis, especially, postnatally. Central tolerance occurs in the thymic medulla via a mechanism of negative selection which leads to the eradication of autoreactive T cell clones. Mechanisms of Action: Such a tolerogenic event relies on Fas-mediated apoptosis of autoreactive T cell clones operated by thymic dendritic cells (DCs), on the one hand. On the other hand, activated thymic T regulatory (Treg) cells in cooperation with medullary thymic epithelial cells and DCs suppress autoreactive T cell clones. Peripherally, different types of Treg cells exert the so-called peripheral tolerance towards autoreactive T cell clones which may have escaped from negative selection mechanisms. At the same time, peripheral Treg cells activated by tolerogenic DC have antiinflammatory activities, especially in the intestine towards food and microbial antigens. Drug Targeting: Various natural and dietary products, such as vitamins (A, C, D), lactobacilli and polyphenols will be described for their tolerogenic capacity to attenuate the inflammatory pathway, as observed in preclinical and clinical studies.

Background: Secondary lymphoid organs (SLO) are distributed in many districts of the body and, especially, lymph nodes, spleen and gut-associated lymphoid tissue are the main cellular sites. On the other hand, tertiary lymphoid organs (TLO) are formed in response to inflammatory, infectious, autoimmune and neoplastic events. Developmental Studies: In the present review, emphasis will be placed on the developmental differences of SLO and TLO between small intestine and colon and on the role played by various chemokines and cell receptors. Undoubtedly, microbiota is indispensable for the formation of SLO and its absence leads to their poor formation, thus indicating its strict interaction with immune and non immune host cells. Furthermore, food antigens (for example, tryptophan derivatives, flavonoids and byphenils) bind the aryl hydrocarbon receptor on innate lymphoid cells (ILCs), thus promoting the development of postnatal lymphoid tissues. Also retinoic acid, a metabolite of vitamin A, contributes to SLO development during embryogenesis. Vitamin A deficiency seems to account for reduction of ILCs and scarce formation of solitary lymphoid tissue. Translational Studies: The role of lymphoid organs with special reference to intestinal TLO in the course of experimental and human disease will also be discussed. Future Perspectives: Finally, a new methodology, the so-called “gut-in-a dish”, which has facilitated the in vitro interaction study between microbe and intestinal immune cells, will be described.

Antimicrobial Peptides (AMPs) are produced by a variety of human immune and non immune cells in health and disease. In virtue of their antimicrobial activity, AMPs have been exploited in human disease and here this aspect will extensively be described. AMPs in comparison to antibiotics possess a larger spectrum of antimicrobial activity without inducing microbial resistance. Therefore, their use in the course of antibiotic-resistant infections is justified. AMP activity in early life, in the airways, in the oral and gastro-enteric system, in the skin and in the female reproductive tract, respectively, will be elucidated. In addition, the use of AMPs in sepsis will be discussed due to the frequency of this pathological condition characterized by multiple organ dysfunctions. Finally, the evidence that AMPs represent valid substitutes of antibiotics will be provided and a series of novel substances able to reinforce the innate immune response in different clinical settings will be discussed.

Background: Due to the sensitizing constituents of eye cosmetics, allergic contact dermatitis is considered a frequent cause of eyelid dermatitis. An association between eyelid dermatitis and nickel contained in make-ups remains controversial. Objective: The study aimed to assess the association between nickel allergy, the use of pigmented makeup products and self-reported eyelid dermatitis. Method: This multi-centric, cross-sectional study enrolled 165 women sensitized to nickel (patients) and 103 women without intolerance to metals (controls). We recorded: demographics, atopy, use of pigmented eye cosmetics (mascara, eyeshadow, eyeliner, eyebrow pencil), and previous eyelid dermatitis. Among the patients, any co-sensitization to cosmetics or metals was recorded. Results: 87.3% of the patients and 91.3% of the controls reported their use of eye make-up; 44.9% and 52.4%, respectively, reported previous episodes of eyelid dermatitis, without significant differences. The occurrence of eyelid dermatitis was significantly associated with the use of eye make-up products, both in general and considering each product separately. Age, atopy, or co-sensitization to other metals or cosmetics did not affect the occurrence of eyelid dermatitis. Conclusion: Nickel allergy should not be considered the main risk factor for eyelid dermatitis. The use of pigmented eye make-up may be a triggering factor for eyelid dermatitis, probably due to an irritant action.

Background:Drugs of abuse affect both central nervous system (CNS) and peripheral immune function. Besides the involvement of dopamine and glutamate systems, chronic exposure to drugs of abuse alters immune homeostasis, promoting a pro-inflammatory status. At the same time, impaired peripheral immunity leads to an increased susceptibility to infections in drug abusers.Discussion:There is evidence that certain drugs, such as opioids, activate microglial cells and astrocytes which, in turn, provoke central neuroinflammation. Particularly, opioids bind the Toll-like receptor (TLR)-4 with increased expression of nuclear factor kappa-light-chain-enhancer of activated B cells and release of pro-inflammatory cytokines. Peripheral mediators released by immune cells also contribute to aggravate central neuroinflammation.Conclusion:These are based either on the inhibition of TLR-4 activation by drugs of abuse or on the correction of dopamine and glutamate pathways. Finally, a hypothetic nutraceutical intervention with polyphenols in view of their anti-inflammatory and anti-oxidant properties will be outlined as an adjuvant treatment for drugs of abuse-related disorders.