Polyphenols from Mediterranean Plants: Biological Activities for Skin Photoprotection in Atopic Dermatitis, Psoriasis, and Chronic Urticaria.

Polyphenols are a diverse class of natural compounds that are widely distributed in various fruits, vegetables, and herbs. They possess antioxidant and anti-inflammatory properties and bring benefits in the prevention and treatment of various diseases. Studies suggested that polyphenols may improve cardiovascular health and may have neuroprotective effects. The Mediterranean region is a vast area. Although the territory encompasses a wide variety of cultures and dietary patterns, there are some commonalities in terms of the plant-based foods and their polyphenol content. Such polyphenols have been studied for their potential photoprotective effects on the skin. We focused on nutraceutical effects of Mediterranean plants in skin photoprotection in atopic dermatitis, psoriasis, and chronic urticaria. Results highlight the importance of exploring natural compounds for therapeutic purposes. The wide variety of polyphenols found in different foods and plants allows for a diverse range of pharmacological effects. The Mediterranean diet, rich in polyphenol-containing foods, is associated with a lower incidence of various chronic diseases, including dermatological conditions. While more research is needed to fully understand the mechanisms of action and optimal dosing of polyphenols, there is initial evidence to support their potential use as adjunctive therapy for atopic dermatitis, psoriasis, and chronic urticaria.

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.

Nutraceuticals against Oxidative Stress in Autoimmune Disorders.

Antioxidant mechanisms are constituted of enzymes, endogenous, and non-enzymatic, exogenous, which have the role of counterbalancing oxidative stress. Intake of these compounds occurs in the diet. Vegetables, plants, and fruits contain a wide range of alkaloids, polyphenols, and terpenoids which are called "phytochemicals". Most of these substances are responsible for the positive properties of fruits and vegetables, which are an essential part of a healthy life with roles in ameliorating chronic illnesses and favoring longevity. Nutraceuticals are substances contained in a food or fragment of it influencing health with positive effects on health helping in precenting or treating disorders. We conducted a review illustrating the principal applications of nutraceuticals in autoimmune disorders. Literature reported several studies about exogenous dietary antioxidant supplementation in diverse autoimmune diseases such as rheumatoid arthritis, lupus, diabetes, and multiple sclerosis. In these pathologies, promising results were obtained in some cases. Positive outcomes were generally associated with a reduction of oxidative stress parameters and a boost to antioxidant systems, and sometimes with anti-inflammatory effects. The administration of exogenous substances through food derivates or dietary supplements following scientific standardization was demonstrated to be effective. Further bias-free and extended studies should be conducted that include ever-increasing oxidative stress biomarkers.

The Impact of Immunological Checkpoint Inhibitors and Targeted Therapy on Chronic Pruritus in Cancer Patients.

Although pruritus may sometimes be a consequential situation to neoplasms, it more frequently emerges after commencing chemotherapy. In this review, we present our analysis of the chemotherapy treatments that most often induce skin changes and itching. After discussing conventional chemotherapies capable of inducing pruritus, we present our evaluation of new drugs such as immunological checkpoint inhibitors (ICIs), tyrosine kinase inhibitors, and monoclonal antibodies. Although ICIs and targeted therapy are thought to damage tumor cells, these therapies can modify homeostatic events of the epidermis and dermis, causing the occurrence of cutaneous toxicities in treated subjects. In the face of greater efficacy, greater skin toxicity has been reported for most of these drugs. A remarkable aspect of some reports is the presence of a probable correlation between cutaneous toxicity and treatment effectiveness in tumor patients who were treated with novel drugs such as nivolumab or pembrolizumab. Findings from these experiments demonstrate that the occurrence of any grade of skin side effects can be considered as a predictor of a better outcome. In the near future, studies on the relationship between the onset of skin alterations and outcomes could open new perspectives on the treatment of neoplasms through specific target therapy.

Changes in Serum Interleukin-8 and sRAGE Levels in Multiple Myeloma Patients.

BACKGROUND/AIM: Although numerous cytokines influence proliferation and progression of multiple myeloma (MM), a relevant action in the onset of the disease also seems to be played by the oxidative state. PATIENTS AND METHODS: In the present study we evaluated the concentrations of interleukin-8 (IL-8) and soluble receptor of advanced glycation end products (sRAGE) in patients with MM, assessing the existing variations with respect to a control group and the possible existence of correlations between these molecules and the biological variables or the presence of a correlation between IL-8 and sRAGE. The study was conducted on 33 patients affected by MM compared to 39 healthy subjects. RESULTS: IL-8 and sRAGE levels were significantly higher in MM patients compared to healthy subjects. sRAGE and IL-8 evidence no significant linear correlation. Furthermore, IL-8 was significantly increased in both sexes, but we found a slight variation for females compared to males. CONCLUSION: IL-8 could play an important role in the onset of MM and the progression of bone disease, while the increased sRAGE values would seem to have a protective action in MM patients. Further studies on animal models may clarify the real impact of introducing modulation of IL-8 and sRAGE levels.

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.

Lymphocyte Subsets and Inflammatory Cytokines of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma.

Almost all multiple myeloma (MM) cases have been demonstrated to be linked to earlier monoclonal gammopathy of undetermined significance (MGUS). Nevertheless, there are no identified characteristics in the diagnosis of MGUS that have been helpful in differentiating subjects whose cancer may progress to a malignant situation. Regarding malignancy, the role of lymphocyte subsets and cytokines at the beginning of neoplastic diseases is now incontestable. In this review, we have concentrated our attention on the equilibrium between the diverse lymphocyte subsets and the cytokine system and summarized the current state of knowledge, providing an overview of the condition of the entire system in MGUS and MM. In an age where the therapy of neoplastic monoclonal gammopathies largely relies on drugs capable of acting on the immune system (immunomodulants, immunological checkpoint inhibitors, CAR-T), detailed knowledge of the the differences existing in benign and neoplastic forms of gammopathy is the main foundation for the adequate and optimal use of new drugs.

MiR-21 upregulation increases IL-8 expression and tumorigenesis program in airway epithelial cells exposed to cigarette smoke.

BACKGROUND: Cigarette smoke exposure, increasing Toll-like receptor 4 (TLR4) and reactive oxygen species (ROS), promotes inflammatory responses in airway epithelial cells. Chronic inflammation, microRNA (miRNA), and oxidative stress are associated with cancer development. AIMS: The present study was aimed to explore whether cigarette smoke exposure, altering miR-21 expression, promoted inflammatory responses and tumorigenesis processes in airway epithelial cells. METHODS: Airway normal and cancer epithelial cells (16HBE and A549) were exposed to cigarette smoke extracts (CSE) or with/without agomiR-21, and then it was assessed: a) miR-21 expression; b) signal transducer and activator of transcription 3 (STAT3) nuclear protein expression and ERK1/2 activation; c) IL-8 gene expression and protein release. An antagonist of TLR4 (CLI-095) and the antioxidant flavonoid, apigenin, were also included to evaluate miR-21 expression in CSE exposed cells. RESULTS: It was demonstrated that: a) A549 cells constitutively expressed higher levels of miR-21 and IL-8; b) CSE increased STAT3 nuclear expression in 16HBE; c) in both cell lines, CSE and agomiR-21 increased: miR-21 expression; ERK1/2 activation and IL-8 gene expression and protein release; d) TLR4 inhibition counteracted the effects of CSE on miR-21 in A549; e) apigenin reduced miR-21 and IL-8 gene expression in both cell lines. CONCLUSIONS: Data herein provided identified for the first time new mechanisms supporting the crucial role of cigarette smoke-induced miR-21 expression in the amplification of inflammatory responses and in tumorigenesis processes within the airways.

Interleukin-33 Involvement in Nonsmall Cell Lung Carcinomas: An Update.

Lung carcinogenesis is a multistep process involving genetic mutations and epigenetic changes, with the acquisition of a malignant phenotype characterized by apoptosis resistance, unregulated proliferation and differentiation, invasion, and metastatic abilities. However, neoplastic development and progression seem to be aided by non-neoplastic cells; the molecules they produced can either promote the immune response or, alternatively, support tumor pathogenesis. Consequently, the relative contribution of tumor-associated inflammatory pathways to cancer development has become crucial information. Interleukin-33 (IL-33) is an IL-1-like alarmin, and it is a ligand for the suppressor of tumorigenicity 2 (ST2) receptor. IL-33 functions as a dual role cytokine with the ability to induce T-helper-type 2 (Th2) immune cells and translocate into the nucleus, suppressing gene transcription. Although its function in immunity- and immune-related disorders is well known, its role in tumorigenesis is still debated. The IL-33/ST2 axis is emerging as a powerful modulator of the tumor microenvironment (TME) by recruiting immune cells, able to modify the TME, supporting malignant proliferation or improving antitumor immunity. In the present review, we discuss IL-33's potential role in lung carcinogenesis and its possible application as a therapeutic target.

Evaluation of the AGE/sRAGE Axis in Patients with Multiple Myeloma.

Glycative stress influences tumor progression. The aim of the present study was to evaluate the advanced glycation end products/soluble receptor of advanced glycation end products (AGE/sRAGE) axis in patients with multiple myeloma (MM). Blood samples were taken from 19 patients affected by MM and from 16 sex-matched and age-matched healthy subjects. AGE and sRAGE axis were dosed in patients with MM and matched with controls. AGEs were measured by spectrofluorimetric methods. Blood samples for the determination of sRAGE were analyzed by ELISA. AGE levels were significantly reduced in patients with respect to controls. Instead, sRAGE was significantly elevated in patients affected by MM compared to healthy subjects. Moreover, we showed that there was a statistically significant difference in sRAGE according to the heavy and light chain. IgA lambda had significantly higher sRAGE values than IgA kappa, IgG kappa, and IgG Lambda MM patients. From our data emerges the role of the sRAGE/AGE axis in MM. Since AGE is a positive regulator of the activity of RAGE, circulating sRAGE concentrations may reflect RAGE expression and may be raised in parallel with serum AGE concentrations as a counter-system against AGE-caused tissue damage. Serum concentrations of AGE and sRAGE could therefore become potential therapeutic targets.

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.

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.

A prospective, randomized, comparative study of intravenous alone and combined intravenous and intraarticular administration of tranexamic acid in primary total knee replacement.

BACKGROUND: Studies on the use of tranexamic acid (TXA) to improve clinical outcomes after joint arthroplasty have reported contrasting results between intravenous (IV) TXA alone and combined IV and intraarticular (IA) administration. We compared the effectiveness of the 2 methods in providing higher postoperative hemoglobin (Hb) levels in patients undergoing primary total knee arthroplasty (TKA). METHODS: A total of 100 TKA patients were randomly assigned to receive either IV TXA alone (group 1) or combined IV and topical IA TXA (group 2). Hb and hematocrit levels were measured before and after surgery. The amount of drained blood and transfused blood for the 2 groups was compared. RESULTS: The Hb level was significantly higher at postoperative day 4, together with a positive, albeit not significant, trend toward less postoperative blood loss in the group that received combined IV and IA TXA. No postoperative infections or deep venous thrombosis events occurred. CONCLUSIONS: This study reinforces evidence that, as compared to IV TXA alone, combined IV and IA administration of TXA has a synergic effect, leading to higher postoperative Hb levels without influencing drug safety in TKA patients.

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.