IL-33 genetics and epigenetics in immune-related diseases.

Interleukin-33 (IL-33) is a 30KDa protein, which belongs to the Interleukin-1 cytokine family. It is a crucial regulator of innate and adaptive immune responses. This interleukin is additionally involved in the inflammatory reaction versus helminthic infections. Interleukin 33 acts on group 2 innate lymphoid cells and mast cells macrophages, dendritic cells and CD4 + Th2 cells eliciting a type 2 immune response. Moreover, the cytokine can activate the ST2 of Tregs, demonstrating its ability to downregulate inflammation. IL-33 has also an intracellular function by regulating transcription. The active IL-33 doesn't have a signal peptide, so it's not released across a normal secretory pathway; the interleukin is released when the cells are damages and acts like an "alarmin". Its influence on immune activation could be slightly adjusted via fine epigenetic interactions involving cascade pathways and immune genes. Due to the diverse data emerged from different experimental research, we decided span literature to clarify, as much as possible, how IL-33 is influenced by and influence gene expression. The authors reported how its balance is influenced, according to the tissue considered. Fundamental for immune-related diseases, IL-33 has a key role in controlling inflammation. The understanding of the cytokine switch will be fundamental in a near future in order to block or activate some immune pathways. In fact, we could control interleukins effects not only by monoclonal antibodies but also by using siRNA or miRNAs for silencing or expressing key genes.

IL-31, itch and hematological malignancies.

Pruritus is one of the most common symptoms experienced by neoplastic patients. The pathogenesis of neoplastic itch is complex and multifactorial and could be due to an unbalanced production of humoral mediators by altered immune effector cells. IL-31 is a pro-inflammatory cytokine produced by CD4 + T helper cells. The aim of this review was to evaluate the role of this Th2 cytokine and its receptor IL-31RA, in the onset of neoplastic pruritus. We analysed scientific literature looking for the most relevant original articles linking IL-31to itch in oncologic diseases. Interleukin-31 seems to be a main itch mediator in several hematologic disease such as Cutaneous T cells lymphomas. In these patients IL-31 was positively linked to itch level, and IL-31 matched with disease stage. IL-31 seems to play an important role in the signalling pathway involved in pruritus, but it is also suggested to play a proinflammatory and immunomodulatory role which could play a part in the progression of the neoplastic disease. Further studies will be fundamental in facing pruritus in oncologic patients, since this problem compromise their quality of life worsening an already critic picture.

A spotlight on lime: a review about adverse reactions and clinical manifestations due to Citrus aurantiifolia.

Lime (Citrus aurantiifolia) is a plant belonging to the family of Rutaceae and to the genus Citrus. The fruit is widely used in the United States, Mexico, Southeast Asia, Latin America, but is increasingly widespread all over the world. It is used as a fresh fruit, in the preparation of foods, sweets and drinks and its oils are used in the cosmetic and pharmaceutical industry. The main adverse reactions to lime seem to be represented by contact dermatitis, allergic and phototoxic type. In the context of allergic forms, several allergens have been identified in the citrus family, the main one being limonene, but no noteworthy cross-reactivity has been identified. However, a case of fruit protein contact dermatitis has been described, showing sensitization to other fruits, such as kiwi, avocado, pineapple and apple. There are several molecules responsible for phototoxic reactions and mainly belonging to the coumarin and furocoumarins families. Reactions related to ingesting the fruit or inhaling pollen from the tree appear to be rare, as there are no known cases reported in the literature. The increasing diffusion of lime in Europe must pay attention to possible adverse reactions due to contact with this fruit, which seem destined to increase in future years. Further importance must be placed on patch tests and on the possibility of using alternative extracts to classic fragrance mixes.

IL-33 in Mental Disorders.

Mental disorders are common in the general population; every year about 25% of the total European population is affected by a mental condition. The prevalence of psychiatric disorders might be underestimated. Emerging evidence highlights the role of immune response as a key factor in MDs. Immunological biomarkers seem to be related to illness progression and to treatment effectiveness; several studies suggest strong associations among IL-6, TNFa, S100b, IL 1b, and PCR with affective or schizophrenic disorders. The purpose of this review is to examine and to understand the possible link between mental disorders and interleukin 33 to clarify the role of this axis in the immune system. We found 13 research papers that evaluated interleukin 33 or interleukin 31 levels in subjects affected by mental disorders. Eight studies investigated cytokines in affective disorders. Three studies measured levels of IL-33 in schizophrenia and two studies focused on patients affected by autism spectrum disorders. Alterations in brain structure and neurodevelopmental outcome are affected by multiple levels of organization. Disorders of the autoimmune response, and of the IL-33/31 axis, may therefore be one of the factors involved in this process. These results support the evidence that alarmins, particularly the IL-33/31 axis, need more consideration among researchers and practitioners.

The leukotriene receptor antagonist Montelukast can induce adverse skin reactions in asthmatic patients.

Montelukast the leukotriene receptor antagonist is an anti-inflammatory drug that causes bronchodilation and for this reason it is used to improve inflammatory states in asthma and allergic rhinitis. Montelukast is generally considered a safe drug with the occurrence of a few adverse drug reactions (ADRs) and anti-leucotrienes are usually well-tolerated by adults and young patients. Starting from these premises the purpose of this review is so give un up-to-date scenario about skin adverse reactions due to Montelukast administration. Only few cases were reported during last years, however interestingly some recent reports let us enlarging our ADR data about Montelukast. We decided to divide the paragraph into sections evaluating the following skin lesions: vasculitic lesions, rash, urticaria and angioedema. As described in the results, CSS were the most frequent cases reported, belonging to the Vasculitis category. We speculated several mechanisms leading to the spread of the skin reactions. Montelukast still remains a safe drug used for the treatment of severe and moderate asthma. However, for some reasons still in course of analysis, in rare cases patients could develop ADR. Among these, about half of the patients show skin signs as rash, vescicles, bullous skin, purpura, maculopapular cutis, erythematous exanthema, urticaria and angioedema. Most of these symptoms are a consequence of the onset of a vasculitis as CSS and allergic granulomatous angiitis. In many cases the onset of the reactions happen within the first months of intake. For this reason, the prescribing physicians should be alert for signs, symptoms and genetic predisposition of these skin diseases.

Association of different oral anticoagulants use with renal function worsening in patients with atrial fibrillation: A multicentre cohort study.

AIMS: To investigate the decline of estimated glomerular filtration rate (eGFR) in patients with atrial fibrillation (AF) treated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs). METHODS: Multicentre prospective cohort study including 1667 patients with nonvalvular AF. The eGFR was assessed by the CKD-EPI formula at baseline and during follow-up. The primary endpoint of the study was the median annual decline of eGFR according to VKA (n = 743) or NOAC (n = 924) use. As secondary endpoints, we analysed the transition to eGFR <50 mL/min/1.73 m2 and the eGFR class worsening. RESULTS: Median age was 73.7 ± 9.1 years and 43.3% were women. VKA-treated patients showed an eGFR decline of -2.11 (interquartile range [IQR] -5.68/-0.62), which was -0.27 (IQR -9.00/4.54, P < 0.001 vs VKAs), -1.21 (IQR -9.98/4.02, P = 0.004 vs VKAs) and -1.32 (IQR -8.70/3.99, P = 0.003 vs VKAs) in patients on dabigatran, rivaroxaban and apixaban, respectively. Transition to eGFR <50 mL/min/1.73 m2 was lower in dabigatran- and apixaban-treated patients: odds ratio (OR) 0.492, 95% confidence interval (CI) 0.298-0.813, P = 0.006 and OR 0.449, 95% CI 0.276-0.728, P = 0.001, respectively. A lower rate of eGFR class worsening was found in all groups of NOACs compared to VKAs. No difference between full and reduced dose of NOAC was found. Subgroup analysis showed that the association between NOAC and eGFR changes was markedly reduced in diabetic patients. CONCLUSION: Patients prescribed NOACs showed a lower decline of renal function compared to those prescribed VKAs. This effect was partially lost in patients with diabetes.

Urticaria: recommendations from the Italian Society of Allergology, Asthma and Clinical Immunology and the Italian Society of Allergological, Occupational and Environmental Dermatology.

BACKGROUND: Urticaria is a disorder affecting skin and mucosal tissues characterized by the occurrence of wheals, angioedema or both, the latter defining the urticaria-angioedema syndrome. It is estimated that 12-22% of the general population has suffered at least one subtype of urticaria during life, but only a small percentage (estimated at 7.6-16%) has acute urticaria, because it is usually self-limited and resolves spontaneously without requiring medical attention. This makes likely that its incidence is underestimated. The epidemiological data currently available on chronic urticaria in many cases are deeply discordant and not univocal, but a recent Italian study, based on the consultation of a national registry, reports a prevalence of chronic spontaneous urticaria of 0.02% to 0.4% and an incidence of 0.1-1.5 cases/1000 inhabitants/year. METHODS: We reviewed the recent international guidelines about urticaria and we described a methodologic approach based on classification, pathophysiology, impact on quality of life, diagnosis and prognosis, differential diagnosis and management of all the types of urticaria. CONCLUSIONS: The aim of the present document from the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) is to provide updated information to all physicians involved in diagnosis and management of urticaria and angioedema.

Role of Alarmins in the Pathogenesis of Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare chronic autoimmune disease associated with significant morbidity and mortality. Two main subsets of SSc are recognized: (i) diffuse cutaneous SSc with rapidly progressive fibrosis of the skin, lungs, and other internal organs; and (ii) limited cutaneous SSc, which is dominated by vascular manifestations, with skin and organ fibrosis generally limited and slowly progressing. In spite of intense investigation, both etiology and pathogenesis of SSc are still unknown. Genetic and environmental factors, as well as abnormalities of immune functions, are strongly suggested for etiology, while microvascular abnormalities, immune system activation, and oxidative stress are suggested for the pathogenesis. Recently, it has been found that a multitude of mediators and cytokines are implicated in the fibrotic processes observed in SSc. Among these, a central role could be exerted by "alarmins", endogenous and constitutively expressed proteins/peptides that function as an intercellular signal defense. This review describes, in a detailed manner, the role of alarmins in the pathogenesis of scleroderma.

PPI adverse drugs reactions: a retrospective study.

Proton pump inhibitors (PPIs) are drugs capable of blocking the gastric pump H,K-ATPase in order to inhibit gastric acid secretion. Omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole belong to PPIs category. Although PPIs have a good safety profile, allergic reactions to these molecules can occur. The real rate of hypersensitive reactions to PPIs is unknown. The aim of this retrospective study is to evaluate the rate of hypersensitive reactions to PPIs in patients admitted to our Unit between 2008 and 2013 with a history of drug hypersensitivity. From a database of 1229 patients (921 women, 308 men) with adverse drug reaction we extrapolated the data about PPI reactions. Twelve patients (10 female, 2 men) had a positive history for hypersensitive reaction to PPI. Pantoprazole was the most frequently PPI involved. Based on patient personal history in some cases we performed an oral challenge test for an alternative anti-acid drug and none of them had adverse reactions. According to our experience and according to the literature and pharmacovigilance reports, ADR caused by PPIs are ever increasing. Adverse reactions to these drugs are still under-reported; however, considering the frequency of their prescription worldwide, the risk of severe allergic events is low. Further studies are needed to provide clearer data on the real incidence and prevalence about this matter. This should be useful to help physician in choosing the molecule to prescribe and, in case of hypersensitivity, the alternative molecule to test, also considering the possible cross-reactivity.

The ST2/Interleukin-33 Axis in Hematologic Malignancies: The IL-33 Paradox.

Interleukin (IL)-33 is a chromatin-related nuclear interleukin that is a component of IL-1 family. IL-33 production augments the course of inflammation after cell damage or death. It is discharged into the extracellular space. IL-33 is regarded as an "alarmin" able to stimulate several effectors of the immune system, regulating numerous immune responses comprising cancer immune reactions. IL-33 has been demonstrated to influence tumorigenesis. However, as far as this cytokine is concerned, we are faced with what has sometimes been defined as the IL-33 paradox. Several studies have demonstrated a relevant role of IL-33 to numerous malignancies, where it may have pro- and-less frequently-antitumorigenic actions. In the field of hematological malignancies, the role of IL-33 seems even more complex. Although we can affirm the existence of a negative role of IL-33 in Chronic myelogenos leukemia (CML) and in lymphoproliferative diseases and a positive role in pathologies such as Acute myeloid leukemia (AML), the action of IL-33 seems to be multiple and sometimes contradictory within the same pathology. In the future, we will have to learn to govern the negative aspects of activating the IL-33/ST2 axis and exploit the positive ones.

Involvement of miR-126 in autoimmune disorders.

BACKGROUND: Micro-RNA represent a great family of small non-condign ribonucleic acid molecules; in particular microRNA-126 is an important member of this family and is expressed in many human cells such as cardiomyocytes, endothelial and lung cells. Some studies have shown the implication of miR-126 in cancer, but recently significant progresses have also been made in determining the role of miR-126 regulating immune-related diseases; probably, in a near future, they could potentially serve as diagnostic biomarkers or therapeutic targets. OBJECTIVE: The purpose of this review is to investigate the role of miR-126 in autoimmune diseases, so as to offer innovative therapies. RESULTS: According literature, it was concluded that miRNAs, especially miR-126, are involved in many pathologies and that their expression levels increase in autoimmune diseases because they interfere with the transcription of the proteins involved. Since microRNAs can be detected from several biological sources, they may be attractive as potential biomarkers for the diagnosis, prognosis, disease activity and severity of various diseases. In fact, once confirmed the involvement of miR-126 in autoimmune diseases, it was speculated that it could be used as a promising biomarker. These discovers implicate that miR-126 have a central role in many pathways leading to the development and sustain of autoimmune diseases. Its key role make this microRNA a potential therapeutic target in autoimmunity. CONCLUSION: Although miR-126 relevant role in several immune-related diseases, further studies are needed to clear its molecular mechanisms; the final step of these novel researches could be the blockage or the prevention of the diseases onset by creating of new targeted therapy.

Drug induced Kounis syndrome: does oxidative stress play a role?

BACKGROUND: Kounis syndrome (KS) has been described as the coincidental occurrence of acute coronary syndromes during an allergic reaction with cardiac anaphylaxis. It is caused by inflammatory mediators released after exposure to drugs, food, environmental and other triggers. Oxidative stress occurring in various inflammatory disorders causes molecular damage with the production of advanced oxidation products (AOPPs) and advanced glycation end products (AGEs). CASE PRESENTATION: Markers of oxidative stress were evaluated in a patient who had experienced KS after antibiotic administration in order to investigate the possible role of these molecules in KS. No data, up to now, are available on biomarkers of oxidative stress in patients with drug-induced KS. CONCLUSIONS: AOPPs, but not AGEs, were significantly increased in the KS affected patient compared to controls as already reported in mastocytosis affected patients.

IL-33/IL-31 Axis: A Potential Inflammatory Pathway.

Cytokines play an important role in the regulation of the immune system (adaptive and innate). Given their importance in proinflammatory processes, cytokines have been used for understanding the pathogenesis and as biomarkers in many diseases. IL-31 and IL-33 are still considered novel cytokines. IL-31 controls signalling and regulates a huge amount of biological functions: it induces proinflammatory cytokines, regulates cell proliferation, and is involved also in tissue remodelling. On the other hand, IL-33 has been identified as an "alarmin" released from the epithelial cells and from different human tissues and organs after a damage following, that is, an inflammatory process. The aim of this literature review is to strengthen the hypothesis about an IL-31/IL-33 axis by evaluating the most recent studies linking these two cytokines. Literature data showed that, in many cases, IL-31 and IL-33 are linked to each other and that their expression is correlated with disease severity. The presence of one interleukin might stimulate the induction of the other, amplifying inflammation and the consequent detrimental processes. In a near future, influencing their balance could be helpful in modulating the first responses of the immune system in order to prevent the development of many inflammation-related diseases.

Chlorinative stress in age-related diseases: a literature review.

Aging is an agglomerate of biological long-lasting processes that result being inevitable. Main actors in this scenario are both long-term inflammation and oxidative stress. It has been proved that oxidative stress induce alteration in proteins and this fact itself is critically important in the pathophysiological mechanisms leading to diseases typical of aging. Among reactive species, chlorine ones such as hypochlorous acid (HOCl) are cytotoxic oxidants produced by activated neutrophils during chronic inflammation processes. HOCl can also cause damages by reacting with biological molecules. HOCl is generated by myeloperoxidase (MPO) and augmented serum levels of MPO have been described in acute and chronic inflammatory conditions in cardiovascular patients and has been implicated in many inflammatory diseases such as atherosclerosis, neurodegenerative conditions, and some cancers. Due to these data, we decided to conduct an up-to-date review evaluating chlorinative stress effects on every age-related disease linked; potential anti-oxidant countermeasures were also assessed. Results obtained associated HOCl generation to the aging processes and confirmed its connection with diseases like neurodegenerative and cardiovascular pathologies, atherosclerosis and cancer; chlorination was mainly linked to diseases where molecular (protein) alteration constitute the major suspected cause: i.e. inflammation, tissue lesions, DNA damages, apoptosis and oxidative stress itself. According data collected, a healthy lifestyle together with some dietary suggestion and/or the administration of nutracetical antioxidant integrators could balance the effects of chlorinative stress and, in some cases, slow down or prevent the onset of age-releated diseases.

Immunosenescence in aging: between immune cells depletion and cytokines up-regulation.

BACKGROUND: The immunosenescence is a relatively recent chapter, correlated with the linear extension of the average life began in the nineteenth century and still in progress. The most important feature of immunosenescence is the accumulation in the "immunological space" of memory and effector cells as a result of the stimulation caused by repeated clinical and subclinical infections and by continuous exposure to antigens (inhalant allergens, food, etc.). This state of chronic inflammation that characterizes senescence has a significant impact on survival and fragility. In fact, the condition of frail elderly occurs less frequently in situations characterized by poor contact with viral infections and parasitic diseases. Furthermore the immunosenescence is characterized by a particular "remodelling" of the immune system, induced by oxidative stress. Apoptosis plays a central role in old age, a period in which the ability of apoptosis can change. The remodelling of apoptosis, together with the Inflammaging and the up-regulation of the immune response with the consequent secretion of pro-inflammatory lymphokines represents the major determinant of the rate of aging and longevity, as well as of the most common diseases related with age and with tumors. Other changes occur in the innate immunity, the first line of defence providing rapid, but unspecific and incomplete protection, consisting mostly of monocytes, natural killer cells and dendritic cells, acting up to the establishment of a adaptive immune response, which is slower, but highly specific, which cellular substrate consists of T and B lymphocytes. The markers of "Inflammaging" in adaptive immunity in centenarians are characterized by a decrease in T cells "naive." The reduction of CD8 virgins may be related to the risk of morbidity and death, as well as the combination of the increase of CD8+ cells and reduction of CD4+ T cells and the reduction of CD19+ B cells. The immune function of the elderly is weakened to due to the exhaustion of T cell-virgin (CD95-), which are replaced with the clonal expansion of CD28-T cells. CONCLUSIONS: The increase of pro-inflammatory cytokines is associated with dementia, Parkinson's disease, atherosclerosis, diabetes type 2, sarcopenia and a high risk of morbidity and mortality. A correct modulation of immune responses and apoptotic phenomena can be useful to reduce age-related degenerative diseases, as well as inflammatory and neoplastic diseases.

Association between HMGB1 and asthma: a literature review.

BACKGROUND: Recently, some studies demonstrated that HMGB1, as proinflammatory mediator belonging to the alarmin family, has a key role in different acute and chronic immune disorders. Asthma is a complex disease characterised by recurrent and reversible airflow obstruction associated to airway hyper-responsiveness and airway inflammation. OBJECTIVE: This literature review aims to analyse advances on HMGB1 role, employment and potential diagnostic application in asthma. METHODS: We reviewed experimental studies that investigated the pathogenetic role of HMGB in bronchial airway hyper-responsiveness, inflammation and the correlation between HMGB1 level and asthma. RESULTS: A total of 19 studies assessing the association between HMGB1 and asthma were identified. CONCLUSIONS: What emerged from this literature review was the confirmation of HMGB-1 involvement in diseases characterised by chronic inflammation, especially in pulmonary pathologies. Findings reported suggest a potential role of the alarmin in being a stadiation method and a marker of therapeutic efficacy; finally, inhibiting HMGB1 in humans in order to contrast inflammation should be the aim for future further studies.

Interleukin 31 and skin diseases: A systematic review.

BACKGROUND: Although the pathophysiology of pruritus has been extensively studied in recent years, with many resultant advancements, management of pruritus is still enigmatic, particularly in chronic cutaneous diseases, such as atopic dermatitis, chronic urticaria, allergic contact dermatitis, cutaneous T-cell lymphoma, and uremic pruritus. The recent finding of the involvement of interleukin (IL) 31 in the pathogenesis of chronic pruritus has provided a novel approach to the management of chronic inflammatory skin disorders. The present report provided an in-depth overview of the role of IL-31 in chronic skin diseases and the possible diagnostic and therapeutic applications in the management of these diseases. METHODS: A systematic review of IL-31 was conducted by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A review of a total of 45 published research articles revealed that the majority of these articles focused on the role of IL-31 in causation of pruritus and in the worsening of the disease in atopic dermatitis. Other publications examined interleukin in other pruritic diseases (cutaneous T-cell lymphoma, uremic pruritus, allergic contact dermatitis, chronic urticaria). In almost every disease, IL-31 levels were reported to be correlated with the pathology and often with pruritus. The cutaneous injection of IL-31 resulted in a long-lasting itching sensation, and the use of monoclonal antibodies that targeted IL-31 led to a reduction in pruritus. CONCLUSION: The use of monoclonal antibodies against mediators involved in the pathogenesis of chronic skin diseases has shown promising results. Antibodies that target IL-31, in particular, its receptor A, showed interesting results in atopic dermatitis and decreased pruritus. In subsequent years, the use of these new therapeutic strategies could change the scenario of pruritic skin diseases. However, further studies are needed to more rigorously examine the effects of IL-31 cascade blockage in different chronic skin diseases and to confirm efficacy and the safety of these new therapeutic approaches.

Involvement of microRNAs in skin disorders: A literature review.

BACKGROUND: miRNAs are a class of noncoding RNA molecules that modulate gene expression after transcription. It is known that miRNAs are involved in various cellular processes of both normal and diseased skin. Recently, differential expressions of miRNAs have been reported and associated with several immunologic and inflammatory disorders, which indicate a common role in fundamental biologic processes. OBJECTIVE: To collect and review data from the literature on involvement of miRNA in inflammatory skin disorders. METHODS: A bibliographic search of scientific literature was carried out independently by two researchers in scientific data bases and search engines. The MeSH terms used were the following: "microRNAs" combined with "skin," "dermatitis," "urticaria," "eczema," "hypersensitivity." All research articles from inception until April 2016 were considered. RESULTS: A total of 11 research articles on the study of miRNAs in inflammatory skin disorders (atopic dermatitis, delayed-type hypersensitivity, eczema, toxic epidermal necrolysis) were identified. All the studies confirmed the main role of endogenous noncoding RNAs in diseases such as atopic dermatitis, allergic contact dermatitis, eczema, and toxic epidermal necrolysis. CONCLUSION: The miRNAs seem to influence regulatory mechanisms of inflammation in both inducing and contrasting acute and chronic skin inflammation. They also seem to be useful instruments in identifying and staging diseases such as dermatitis and other inflammatory skin diseases. Also, the potential application of miRNAs in genetic therapies demonstrated its efficacy on animal models.

Involvement of new oxidative stress markers in chronic spontaneous urticaria.

INTRODUCTION: Oxidative stress is a result of an imbalance between endogenous production of free reactive oxygen species and reduced effectiveness of antioxidant defence mechanisms. Advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) are compounds formed by transformation of macromolecules, including proteins which can serve as markers of oxidative stress and inflammation in several diseases. AIM: To investigate the role of AGEs and AOPPs as new markers of oxidative stress and inflammation in patients with chronic spontaneous urticaria (CSU). MATERIAL AND METHODS: Advanced glycation end products and AOPP levels were determined in the sera of 85 patients with CSU and 64 healthy controls, using spectrofluorimetry and spectrophotometry, respectively. RESULTS: Advanced oxidation protein products levels in patients were statistically higher than those in controls. These levels were not affected by the presence of positive autologous serum test results or autologous plasma test results. No statistically significant differences were found between AGE levels in patients and controls. CONCLUSIONS: Formation of AGEs and AOPPs may be accelerated in immunological and allergic disorders. Depending on the sites evaluated, the presence or absence of oxidative stress in chronic urticaria is controversial. To our knowledge, this is the first study showing the possible involvement of AOPPs in CSU. The different behaviour observed for these two biomarkers is very likely due to the activation of specific related biochemical pathways associated with the condition under study.

Pathophysiological mechanism and therapeutic role of S100 proteins in cardiac failure: a systematic review.

S100 proteins are a family of highly acidic calcium-binding proteins involved in calcium handling in many tissues and organs. Some of these proteins are highly expressed in cardiac tissue, and an impairment of some specific S100 proteins has been related to heart failure. To check this hypothesis, we decided to review the literature since 2008 until May 2015. According to the studies collected, recovering S100A1 levels may enhance contractile/relaxing performance in heart failure, reverse negative force-frequency relationship, improve contractile reserve, reverse diastolic dysfunction and protect against pro-arrhythmic reductions of sarcoplasmic reticulum calcium. The safety profile of gene therapy was also confirmed. Increased S100B protein levels were related to a worse outcome in chronic heart failure. S100A8/A9 complex plasma levels, as well as other inflammatory biomarkers, were significantly higher in chronic heart failure patients. S100A2 seems to increase both contractile and relaxation performance in animal cardiomyocytes. Otherwise, S100A6 cardiac expression seems to have no effects on contractility. S100A4 KO mice showed reduced cardiac interstitial fibrosis. Data collected encourage a potential prospective application in human. These proteins could be exploited as biomarkers in stadiation and prognosis of chronic heart failure, as well as therapeutic target to rescue failing heart. Registration details The study protocol has been registered in PROSPERO ( http://www.crd.york.ac.uk/PROSPERO/ ) under registration number CRD42015027932.