Publications by authors named "Marco Casciaro"

41 Publications

IL-33 in Mental Disorders.

Medicina (Kaunas) 2021 Mar 26;57(4). Epub 2021 Mar 26.

School and Operative Unit of Allergy and Clinical Immunology, Policlinico "G. Martino", Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

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.
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http://dx.doi.org/10.3390/medicina57040315DOI Listing
March 2021

Nutraceuticals against Oxidative Stress in Autoimmune Disorders.

Antioxidants (Basel) 2021 Feb 8;10(2). Epub 2021 Feb 8.

Department of Clinical and Experimental Medicine, Unit and School of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy.

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.
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http://dx.doi.org/10.3390/antiox10020261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914737PMC
February 2021

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

Biomedicines 2020 Dec 22;9(1). Epub 2020 Dec 22.

School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

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.
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http://dx.doi.org/10.3390/biomedicines9010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822170PMC
December 2020

Synergic Crosstalk between Inflammation, Oxidative Stress, and Genomic Alterations in BCR-ABL-Negative Myeloproliferative Neoplasm.

Antioxidants (Basel) 2020 Oct 23;9(11). Epub 2020 Oct 23.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have recently been revealed to be related to chronic inflammation, oxidative stress, and the accumulation of reactive oxygen species. It has been proposed that MPNs represent a human inflammation model for tumor advancement, in which long-lasting inflammation serves as the driving element from early tumor stage (over polycythemia vera) to the later myelofibrotic cancer stage. It has been theorized that the starting event for acquired stem cell alteration may occur after a chronic inflammation stimulus with consequent myelopoietic drive, producing a genetic stem cell insult. When this occurs, the clone itself constantly produces inflammatory components in the bone marrow; these elements further cause clonal expansion. In --negative MPNs, the driver mutations include , , and . Transcriptomic studies of hematopoietic stem cells from subjects with driver mutations have demonstrated the upregulation of inflammation-related genes capable of provoking the development of an inflammatory state. The possibility of acting on the inflammatory state as a therapeutic approach in MPNs appears promising, in which an intervention operating on the pathways that control the synthesis of cytokines and oxidative stress could be effective in reducing the possibility of leukemic progression and onset of complications.
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http://dx.doi.org/10.3390/antiox9111037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690801PMC
October 2020

Oxidative stress as a key feature of autoimmune thyroiditis: an update.

Minerva Endocrinol 2020 Dec 24;45(4):326-344. Epub 2020 Sep 24.

Unit of Allergology and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Introduction: Oxidative stress has been proposed as one of the factors concurring in the pathophysiology of autoimmune thyroid diseases. Reactive oxygen species are the main expression of oxidative stress in biological systems, and their production can overcome antioxidant defenses ultimately leading to cell damage, apoptosis, and death. The present review was aimed at describing the state of the art of the relationships between oxidative stress and autoimmune thyroiditis. The most used biomarkers of oxidative stress and their correlation with thyroid function are reported.

Evidence Acquisition: We conducted a search of the literature in the English language starting from 2000, using the following search terms: "Hashimoto thyroiditis," "autoimmune thyroiditis," "hypothyroidism," "hyperthyroidism," "oxidative stress," "oxidants," "antioxidant," "advanced glycation end products." Both clinical studies and animal models were evaluated.

Evidence Synthesis: Data form clinical studies clearly indicate that the balance between oxidants and antioxidants is shifted towards the oxidative side in patients with autoimmune thyroiditis, suggesting that oxidative stress may be a key event in the pathophysiology of the disease, irrespective of thyroid function. Studies in animal models, such as the NOD.H2h4 mouse, confirm that thyroidal accumulation of ROS plays a role in the initiation and progression of autoimmune thyroiditis.

Conclusions: Oxidant/antioxidant imbalance represent a key feature of thyroid autoimmunity. Oxidative stress parameters could be used as biochemical markers of chronic inflammation, to better predict the disease evolution along its natural history. Dietary habits and antioxidant supplements may provide protection from autoimmunity, opening new perspectives in the development of more tailored therapies.
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http://dx.doi.org/10.23736/S0391-1977.20.03268-XDOI Listing
December 2020

S100B in heart diseases.

Cardiovasc Pathol 2020 Nov - Dec;49:107235. Epub 2020 Jun 25.

School and Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University Hospital of Messina "G. Martino", University of Messina, Messina, Italy.

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http://dx.doi.org/10.1016/j.carpath.2020.107235DOI Listing
November 2020

The role of skin and gut microbiome and epigenetic modifications upon skin autoimmune disorders.

Curr Mol Med 2020 Aug 12. Epub 2020 Aug 12.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina. Italy.

Human microbiota and immune system are strictly connected to each other. Several studies demonstrated that normal skin and/or gut floral alterations may have negative consequences upon disease pathogenesis. Indeed, a strong association between skin and gut microbiota alterations and autoimmune diseases was found. Moreover, a significant interplay between microbiome and miRNAs expression was noticed among several conditions. The aim of this review article is to shed new light on some of the commonest skin disorders such as psoriasis, atopic dermatitis, allergic contact dermatitis, with special regards to epigenetic pathogenetic mechanisms such as miRNAs expression and skin and gut microbiome alterations. Indeed, evidence is still lacking regarding these two factors and their possible interactions. We believe their implications may be crucial for screening, early diagnosis and also therapeutic strategies, therefore this field could represent a promising challenge for further studies.
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http://dx.doi.org/10.2174/1566524020666200812222324DOI Listing
August 2020

Role of Alarmins in the Pathogenesis of Systemic Sclerosis.

Int J Mol Sci 2020 Jul 15;21(14). Epub 2020 Jul 15.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy.

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.
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http://dx.doi.org/10.3390/ijms21144985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404317PMC
July 2020

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

Clin Mol Allergy 2020 6;18. Epub 2020 May 6.

5Section of Dermatology, Department of Medicine, University of Perugia, Perugia, Italy.

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.
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http://dx.doi.org/10.1186/s12948-020-00123-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201804PMC
May 2020

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

Br J Clin Pharmacol 2020 12 7;86(12):2455-2463. Epub 2020 Jun 7.

Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

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 m 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 m 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.
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http://dx.doi.org/10.1111/bcp.14350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688543PMC
December 2020

Oxidative Stress and Atopic Dermatitis.

Antioxidants (Basel) 2020 Feb 26;9(3). Epub 2020 Feb 26.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

Atopic dermatitis is a common chronic/chronically relapsing inflammatory skin disease, with increasing worldwide prevalence. Etiopathogenesis is complex and multifactorial, with a mix of genetic, immunological and environmental aspects. Like in other chronic inflammatory diseases, oxidative stress plays an important pathogenetic role. We reviewed in vivo research studies on humans about oxidative stress and atopic dermatitis. Although sometimes contrasting, overall, they suggest that oxidative stress may have a significant role in atopic dermatitis, but our understanding is still incomplete, at least concerning in vivo data, because of limitations of available literature. Research consists of 33 papers published in 28 years, was not always performed on large study populations, represents a limited number of countries and ethnicities-not always in proportion to their size-and is scattered over multiple papers that, in the majority of cases, cannot be pooled and/or compared because many biomarkers were studied, in different tissues and with different methods. Further, larger studies appear warranted and necessary to shed more light on this aspect of atopic dermatitis, which is important not only to improve our understanding of this disease, but also for potential clinical and therapeutic implications.
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http://dx.doi.org/10.3390/antiox9030196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139929PMC
February 2020

Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role.

Cancers (Basel) 2020 Feb 24;12(2). Epub 2020 Feb 24.

Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

B-cell chronic lymphocytic leukemia (B-CLL) is the main cause of mortality among hematologic diseases in Western nations. B-CLL is correlated with an intense alteration of the immune system. The altered functions of innate immune elements and adaptive immune factors are interconnected in B-CLL and are decisive for its onset, evolution, and therapeutic response. Modifications in the cytokine balance could support the growth of the leukemic clone via a modulation of cellular proliferation and apoptosis, as some cytokines have been reported to be able to affect the life of B-CLL cells in vivo. In this review, we will examine the role played by cytokines in the cellular dynamics of B-CLL patients, interpret the contradictions sometimes present in the literature regarding their action, and evaluate the possibility of manipulating their production in order to intervene in the natural history of the disease.
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http://dx.doi.org/10.3390/cancers12020524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072434PMC
February 2020

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

Pulm Pharmacol Ther 2020 02 11;60:101875. Epub 2019 Dec 11.

School and Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pupt.2019.101875DOI Listing
February 2020

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

Int J Mol Sci 2019 Oct 22;20(20). Epub 2019 Oct 22.

School and Division of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University Hospital "G. Martino", Via Consolare Valeria SNC, 98125 Messina, Italy.

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.
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http://dx.doi.org/10.3390/ijms20205226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834139PMC
October 2019

Oxidative stress involvement in psoriasis: a systematic review.

Free Radic Res 2019 Aug 8;53(8):829-840. Epub 2019 Aug 8.

Department of Clinical and Experimental Medicine, School and Unit of Allergy and Clinical Immunology, University of Messina , Messina , Italy.

Psoriasis is a skin chronic inflammatory disease with a complex aetiology. It is characterised by the imbalance of environmental, genetic, and immunologic factors. Reactive oxygen species (ROS) could damage the cell components. The antioxidant system defends the body against ROS; a malfunction of the antioxidant system, together with an increased production of ROS, is involved in the pathogenesis of several diseases such as psoriasis. The purpose of this systematic review is to give an updated scenario about oxidative stress involvement in the psoriatic disease to identify useful biomarkers and to propose innovative therapies. A total of 28 studies were identified. Although several molecules were demonstrated being associated with psoriasis, only a little group resulted being eligible as disease biomarker [malonyldialdehyde (MDA), total oxidative stress, and oxidative stress index]. However, only MDA seems to be the best candidate for a clinical screening of psoriasis patients since it is intimately linked to Psoriasis Area Severity Index. Data suggest that current therapies with drugs, a healthy lifestyle, and the integration of a diet rich in antioxidants help to reduce the damage of oxidative stress caused by psoriasis, especially at the level of the skin. As much as we know, this is the first systematic review evaluating the oxidative stress role in psoriasis.
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http://dx.doi.org/10.1080/10715762.2019.1648800DOI Listing
August 2019

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

Biomolecules 2019 05 25;9(5). Epub 2019 May 25.

School and Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98123 Messina, Italy.

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.
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http://dx.doi.org/10.3390/biom9050203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572046PMC
May 2019

Interleukin-33 serum levels in postmenopausal women with osteoporosis.

Sci Rep 2019 03 7;9(1):3786. Epub 2019 Mar 7.

School and Division of Allergy and Clinical Immunology, Department of Experimental Medicine, University of Messina, Messina, Italy.

There are many cytokines involved in the pathogenesis of osteoporosis. So far IL-33 involvement in osteoporotic patients has not yet been studied. IL-33 is a pro-inflammatory cytokine which mediates several immune functions; its involvement in a wide range of diseases, such as atopic dermatitis, asthma, and rheumatoid arthritis, is now emerging. In view of the crucial role of this cytokine in inflammation and bone remodeling, we measured IL-33 levels in the serum of postmenopausal women with osteoporosis. In 50 postmenopausal osteoporotic patients and 28 healthy postmenopausal control women, serum IL-33 levels were measured by enzyme linked immunosorbent assay. In both patients and controls the bone mineral density (BMD) was measured by double-energy X-ray absorptiometry (DXA). Vitamin D, calcium, alkaline phosphatase (ALP), parathyroid hormone (PTH) serum levels, as well as bone turnover markers, such as C-terminal telopeptide of type 1 collagen (CTX) and N-terminal propeptide of type 1 procollagen (P1NP) were also evaluated. In postmenopausal osteoporotic women IL-33 levels were significantly lower compared to healthy controls (3.53 ± 2.45 vs. 13.72 ± 5.39 pg/ml; P = 0.009) and positively correlated respectively with serum PTH (rho = 0.314; P = 0.026) and P1NP (rho = 0.373; P = 0.011) levels, while a statistically significant inverse correlation was observed between serum IL-33 and CTX levels (rho = -0.455; P = 0.002). Our results thus suggest that IL-33 represents an important bone-protecting cytokine which may be of therapeutic benefit in treating bone resorption.
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http://dx.doi.org/10.1038/s41598-019-40212-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405990PMC
March 2019

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

Antioxidants (Basel) 2019 Mar 4;8(3). Epub 2019 Mar 4.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy.

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.
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http://dx.doi.org/10.3390/antiox8030055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466542PMC
March 2019

PPI adverse drugs reactions: a retrospective study.

Clin Mol Allergy 2019 18;17. Epub 2019 Jan 18.

1School and Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

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.
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http://dx.doi.org/10.1186/s12948-019-0104-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337765PMC
January 2019

Do Alarmins Have a Potential Role in Autism Spectrum Disorders Pathogenesis and Progression?

Biomolecules 2018 12 20;9(1). Epub 2018 Dec 20.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, Messina 98125, Italy.

Autism spectrum disorders (ASDs) represent a disabling condition in early childhood. A number of risk factors were proposed in order to explain their pathogenesis. A multifactorial model was proposed, and data supported the implication of genetic and environmental factors. One of the most accepted speculations is the existence of an imbalance of the immune system. Altered levels of cytokines, chemokines and immunoglobulins were demonstrated in patients with ASDs; in particular, proinflammatory mediators were significantly increased. Alarmins are a multifunctional heterogeneous group of proteins, structurally belonging to specific cells or incorporated by them. They are released in the surrounding tissues as a consequence of cell damage or inflammation. Their functions are multiple as they could activate innate immunity or recruit and activate antigen-presenting cells stimulating an adaptive response. Alarmins are interesting both for understanding the inflammatory process and for diagnostic purposes as biomarkers. Moreover, recent studies, separately, showed that alarmins like interleukin (IL)-33, high-mobility group box 1 (HMGB1), heat-shock protein (HSP) and S100 protein (S100) could play a relevant role in the pathogenesis of ASDs. According to the literature, some of these alarmins could be suitable as biomarkers of inflammation in ASD. Other alarmins, by interfering with the immune system blocking pro-inflammatory mediators, could be the key for ameliorating symptoms and behaviours in autistic disorders.
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http://dx.doi.org/10.3390/biom9010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358895PMC
December 2018

The role of oxidative stress in the biology of melanoma: A systematic review.

Pathol Res Pract 2019 Jan 24;215(1):21-28. Epub 2018 Nov 24.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125, Messina, Italy. Electronic address:

Melanoma is the most aggressive skin tumour, which incidence is rising fast over the year. The metastatic stage of disease is extremely difficult to treat and the mortality rate is still high. Emerging evidence suggested that oxidative stress (OS) is involved in the pathophysiological pathways of several chronic diseases and in the transformation and progression of many common cancers, including melanoma. In particular, it has emerged that OS interacts with inflammatory and immune response, all taking part in the melanomagenic process. In light of the interest shown by the scientific community for this topic, it was analysed the association between melanoma and oxidative stress. A systematic review was performed according to PRISMA guideline employing PubMed database. It identified n = 29 articles which investigated this aspect. Melanoma cells resulted to have adaptive mechanisms to overcome effects of high reactive oxygen species (ROS) levels. Furthermore, OS influences the metastatic ability of melanoma cells and their resistance to therapy. Nonetheless, the included studies were conducted on heterogeneous patient population and with differences in the design of the studies and in the protocols. Therefore, it is mandatory performing further studies which analyze all the aspect of OS pathways: ROS imbalance, its effect to proliferation and metastasis, role of microenvironment, ROS effect to drug resistance. All this in order to understand the role of oxidative stress in the complex biology of melanoma and to provide possibilities of defining new strategy of therapy.
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http://dx.doi.org/10.1016/j.prp.2018.11.020DOI Listing
January 2019

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

Clin Mol Allergy 2018 1;16:21. Epub 2018 Oct 1.

1Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, AOU Policlinico "G.Martino" Via Consolare Valeria 1, 98124 Messina, Italy.

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.
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http://dx.doi.org/10.1186/s12948-018-0099-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166286PMC
October 2018

Involvement of miR-126 in autoimmune disorders.

Clin Mol Allergy 2018 2;16:11. Epub 2018 May 2.

1School and Division of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, Messina University Hospital, 98125 Messina, Italy.

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.
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http://dx.doi.org/10.1186/s12948-018-0089-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930861PMC
May 2018

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

Mediators Inflamm 2018 11;2018:3858032. Epub 2018 Mar 11.

School and Operative Unit of Allergy and Clinical Immunology, Policlinico "G. Martino", Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

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.
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http://dx.doi.org/10.1155/2018/3858032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866851PMC
September 2018

Involvement of new oxidative stress markers in chronic spontaneous urticaria.

Postepy Dermatol Alergol 2017 Oct 31;34(5):448-452. Epub 2017 Oct 31.

School and Division of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, "G. Martino" University Hospital, Messina, Italy.

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.
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http://dx.doi.org/10.5114/ada.2017.71110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831279PMC
October 2017

The Potential Role of MicroRNAs as Biomarkers in Benign Prostatic Hyperplasia: A Systematic Review and Meta-analysis.

Eur Urol Focus 2019 May 3;5(3):497-507. Epub 2018 Feb 3.

Department of Urology, Federico II University, Naples, Italy.

Context: Benign prostate hyperplasia (BPH) is one of the most common urologic diseases. However, the molecular and cellular mechanisms involving the stromal and epithelial components of the prostate that lead to BPH remain unclear.

Objective: To review and evaluate the evidence implicating microRNAs (miRNAs) in the pathogenesis of BPH.

Evidence Acquisition: A systematic search of the PubMed and Embase databases was performed using the terms "benign prostate hypertrophy and miRNA" or ("benign prostate hypertrophy and microRNAs" or "miRNA" or "miR") on July 31, 2017.

Evidence Synthesis: Sixty-four miRNAs from 37 selected articles were ranked according to p values (p≤0.05). To avoid false positive results, Benjamini-Hochberg correction of p values was performed. Application of the robust rank aggregation method identified miR-221 as significantly associated with BPH (p=0.013). The effect size (ES) was calculated for studies with miR-221 data to generate an estimate of the overall ES and its confidence interval. The ES for miR-221 was measured by the standardized mean difference obtained by dividing the difference in the average gene expression between the PCa and BPH groups by a pooled estimate of standard deviation. The random effects model was used to calculate the pooled ES due to the presence of heterogeneity among studies. Publication bias of the seven included studies was assessed by the Funnel plot and Egger's test and it was detected in the overall analysis of the seven studies (p<0.01). After the trim and fill procedure, Egger's test revealed no evidence of publication bias (p=0.76) CONCLUSIONS: miR-221 has the potential to be used both as a biomarker and novel target in the early diagnosis and therapy of BPH. Technological advances should enable the synthesis of pre-RNA or anti-RNA molecules within carrier vehicles that can be safely delivered into patients. The development of such new pharmacologic therapies should be lastly investigated as possible therapy of one of the most common urologic diseases among elderly men. PATIENT SUMMARY: miR-221 has the potential to be used both as a biomarker and novel target in the early diagnosis and therapy of benign prostate hyperplasia. The development of new pharmacologic therapies enabling the synthesis of anti-miR-221 should be lastly investigated as a possible therapy of one of the most common urologic diseases among elderly men.
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http://dx.doi.org/10.1016/j.euf.2018.01.008DOI Listing
May 2019

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

Clin Mol Allergy 2017 14;15:21. Epub 2017 Dec 14.

Dermatological Clinic, Department of Biomedical Science and Human Oncology, University of Bari Medical School, Policlinico, Italy.

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.
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http://dx.doi.org/10.1186/s12948-017-0077-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731094PMC
December 2017

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

Immun Ageing 2017 14;14:21. Epub 2017 Nov 14.

School and Division of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Policlinico "G. Martino", University of Messina, Messina, Italy.

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.
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http://dx.doi.org/10.1186/s12979-017-0104-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686828PMC
November 2017

Interleukin 31 and skin diseases: A systematic review.

Allergy Asthma Proc 2017 Nov;38(6):401-408

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.
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http://dx.doi.org/10.2500/aap.2017.38.4080DOI Listing
November 2017

Association between HMGB1 and asthma: a literature review.

Clin Mol Allergy 2017 14;15:12. Epub 2017 Jun 14.

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

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.
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http://dx.doi.org/10.1186/s12948-017-0068-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471678PMC
June 2017