Publications by authors named "Giuseppe Terrazzano"

46 Publications

Physiology of Midkine and Its Potential Pathophysiological Role in COVID-19.

Front Physiol 2020 22;11:616552. Epub 2020 Dec 22.

Department of Science, University of Basilicata, Potenza, Italy.

SARS-CoV2 infection not only causes abnormal severe pneumonia but also induces other relevant pathophysiological effects on several tissues and organs. In this regard, the clinical complications observed in COVID-19 include acute coronary syndrome, pulmonary thromboembolism, myocarditis and, in the severe cases, the occurrence of disseminated intravascular coagulation. Literature on COVID-19 highlighted the central role of the Renin Angiotensin Aldosterone System in the determinism of SARS-CoV2 cellular internalization in the target tissues. Lung degeneration and respiratory distress appear to be dependent on the perturbance of physiological mechanisms, such as the uncontrolled release of pro-inflammatory cytokines, a dysregulation of the fibrinolytic coagulative cascade and the hyperactivation of immune effector cells. In this mini review, we address the physiology of Midkine, a growth factor able to bind heparin, and its pathophysiological potential role in COVID-19 determinism. Midkine increases in many inflammatory and autoimmune conditions and correlates with several dysfunctional immune-inflammatory responses that appear to show similarities with the pathophysiological elicited by SARS-CoV2. Midkine, together with its receptor, could facilitate the virus entry, fostering its accumulation and increasing its affinity with Ace2 receptor. We also focus on Netosis, a particular mechanism of pathogen clearance exerted by neutrophils, which under certain pathological condition becomes dysfunctional and can cause tissue damage. Moreover, we highlight the mechanism of autophagy that the new coronavirus could try to escape in order to replicate itself, as well as on pulmonary fibrosis induced by hypoxia and on the release of cytokines and mediators of inflammation, correlating the interplay between Midkine and SARS-CoV2.
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http://dx.doi.org/10.3389/fphys.2020.616552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783444PMC
December 2020

Effect of a Weight Loss Program on Biochemical and Immunological Profile, Serum Leptin Levels, and Cardiovascular Parameters in Obese Dogs.

Front Vet Sci 2020 6;7:398. Epub 2020 Aug 6.

Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy.

This study aimed to investigate the effects of a weight loss program (WLP) on biochemical and immunological profile, and cardiovascular parameters in a cohort of dogs with naturally occurring obesity. Eleven obese dogs [body condition scoring (BCS), ≥7/9] were enrolled into the study and underwent clinical and cardiovascular examination, and blood testing before (T0) and after 6 months (T1) of WLP. Eleven normal weight (BCS, 4/5) healthy dogs were used as a control (CTR) group. Compared to the CTR group, at T0 obese dogs expressed higher serum leptin concentrations ( < 0.0005) that significantly decreased after weight loss ( < 0.005) but remained higher than the CTR group. Furthermore, obese dogs showed considerably lower levels ( < 0.0005) of regulatory T cell (Treg) compared to the CTR group, but they did not change after weight loss at T1. In obese dogs, tumor necrosis factor (TNF)-α and interleukin (IL)-6 concentrations were substantially reduced at T1 ( < 0.0001 and < 0.005). Regarding the cardiovascular parameters, only one obese dog was hypertensive at T0, and systolic blood pressure values showed no significant differences at the end of the WLP. The ratio of interventricular septal thickness in diastole to left ventricle internal diameter in diastole (IVSd/LVIDd) was significantly greater in obese dogs at T0 than in the CTR group ( < 0.005). It decreased after weight loss ( < 0.05). In obese dogs, troponin I level significantly reduced with weight loss ( < 0.05), while endothelin-1 level did not differ statistically. The results suggest that the immune dysregulation in the presence of high leptin levels and reduced number of Treg could affect obese dogs as well as humans. Based on our findings, we may speculate that a more complete immune-regulation restore could be obtained by a greater reduction in fat mass and a longer-term WLP. Finally, left ventricular remodeling may occur in some obese dogs. However, in canine species, further studies are needed to investigate the impact of obesity and related WLP on cardiovascular system.
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http://dx.doi.org/10.3389/fvets.2020.00398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424025PMC
August 2020

T1D progression is associated with loss of CD3CD56 regulatory T cells that control CD8 T cell effector functions.

Nat Metab 2020 02 17;2(2):142-152. Epub 2020 Feb 17.

Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale G. Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.

An unresolved issue in autoimmunity is the lack of surrogate biomarkers of immunological self-tolerance for disease monitoring. Here, we show that peripheral frequency of a regulatory T cell population, characterized by the co-expression of CD3 and CD56 molecules (T), is reduced in subjects with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating T cells is associated with reduced β-cell function and with the presence of diabetic ketoacidosis. As autoreactive CD8 T cells mediate disruption of insulin-producing β-cells, we demonstrate that T cells can suppress CD8 T cell functions by reducing levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of T cells are also altered in T1D children. Together, our findings indicate that T cells constitute a regulatory cell population that controls CD8 effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D.
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http://dx.doi.org/10.1038/s42255-020-0173-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272221PMC
February 2020

Serafino Zappacosta: An Enlightened Mentor and Educator.

Front Immunol 2020 13;11:217. Epub 2020 Feb 13.

Dipartimento di Scienze Mediche Traslazionali, Università di Napoli "Federico II", Naples, Italy.

With this article, the authors aim to honor the memory of Serafino Zappacosta, who had been their mentor during the early years of their career in science. The authors discuss how the combination of Serafino Zappacosta's extraordinary commitment to teaching and passion for science created a fostering educational environment that led to the creation of the "." The review also illustrates how the research on the MHC and the inspirational scientific context in the Zappacosta's laboratory influenced the authors' early scientific interests, and subsequent professional work as immunologists.
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http://dx.doi.org/10.3389/fimmu.2020.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031500PMC
March 2021

Knockdown of PTGS2 by CRISPR/CAS9 System Designates a New Potential Gene Target for Melanoma Treatment.

Front Pharmacol 2019 5;10:1456. Epub 2019 Dec 5.

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

CRISPR/Cas9 has become a powerful method to engineer genomes and to activate or to repress genes expression. As such, in cancer research CRISPR/Cas9 technology represents an efficient tool to dissect mechanisms of tumorigenesis and to discover novel targets for drug development. Here, we employed the CRISPR/Cas9 technology for studying the role of prostaglandin-endoperoxide synthase 2 (PTGS2) in melanoma development and progression. Melanoma is the most aggressive form of skin cancer with a median survival of less than 1 year. Although oncogene-targeted drugs and immune checkpoint inhibitors have demonstrated a significant success in improving overall survival in patients, related toxicity and emerging resistance are ongoing challenges. Gene therapy appears to be an appealing option to enhance the efficacy of currently available melanoma therapeutics leading to better patient prognosis. Several gene therapy targets have been identified and have proven to be effective against melanoma cells. Particularly, PTGS2 is frequently expressed in malignant melanomas and its expression significantly correlates with poor survival in patients. In this study we investigated on the effect of knockdown in B16F10 murine melanoma cells. Our results show that reduced expression of in melanoma cells: ) inhibits cell proliferation, migration, and invasiveness; ) modulates immune response by impairing myeloid derived suppressor cell differentiation; ) reduces tumor development and metastasis . Collectively, these findings indicate that could represent an ideal gene to be targeted to improve success rates in the development of new and highly selective drugs for melanoma treatment.
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http://dx.doi.org/10.3389/fphar.2019.01456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915044PMC
December 2019

Modulation of the functions of myeloid-derived suppressor cells : a new strategy of hydrogen sulfide anti-cancer effects.

Br J Pharmacol 2020 02 27;177(4):884-897. Epub 2019 Nov 27.

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

Background And Purpose: Myeloid-derived suppressor cells (MDSCs) represent a major obstacle to cancer treatment, as they negatively regulate anti-tumour immunity through the suppression of tumour-specific T lymphocytes. Thus, the efficacy of immunotherapies may be improved by targeting MDSCs. In this study, we assessed the ability of hydrogen sulfide (H S), a gasotransmitter whose anti-cancer effects are well known, to inhibit the accumulation and immunosuppressive functions of MDSCs in melanoma.

Experimental Approach: Effects of H S on the host immune response to cancer were evaluated using an in vivo syngeneic model of murine melanoma. B16F10-melanoma-bearing mice were treated with the H S donor, diallyl trisulfide (DATS) and analysed for content of MDSCs, dendritic cells (DCs) and T cells. Effects of H S on expression of immunosuppressive genes in MDSCs and on T cell proliferation were evaluated.

Key Results: In melanoma-bearing mice, DATS inhibited tumour growth, and this effect was associated with a reduction in the frequency of MDSCs in the spleen, in the blood as well as in the tumour micro-environment. In addition, we found that CD8 T cells and DCs were increased. Furthermore, DATS reduced the immuno-suppressive activity of MDSCs, restoring T cell proliferation.

Conclusions And Implications: The H S donor compound, DATS, inhibited the expansion and the suppressive functions of MDSCs, suggesting a novel role for H S as a modulator of MDSCs in cancer. Therefore, H S donors may provide a novel approach for enhancing the efficacy of melanoma immunotherapy.

Linked Articles: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
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http://dx.doi.org/10.1111/bph.14824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024705PMC
February 2020

Clinical and Immunological Response in Dogs Naturally Infected by Treated with a Nutritional Supplement.

Animals (Basel) 2019 Jul 30;9(8). Epub 2019 Jul 30.

Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, 80138 Napoli NA, Italy.

The use of nutraceuticals as immunomodulators in the treatment of visceral leishmaniasis has generated interest in the current approaches to treat the disease. In this clinical and immunological study, we investigated whether the administration of a nutritional supplement mediates the immune-modulatory response in canine leishmaniosis (CL) and improves the clinical outcome of the disease. With this purpose, we analysed T lymphocyte subsets in peripheral blood (PB) of 12 dogs naturally infected by , following treatment with a nutritional supplement. The regulatory T (Treg) cells and the T helper (Th) 1 population were specifically evaluated. The animals underwent complete clinical examination and blood sample collection for haematological, biochemical, serological and immunological analysis before treatment (T0), one month (T30) and 3 months (T90) after the onset of the nutraceutical supplementation. We observed that nutraceutical supplementation was associated with immunomodulation of Th1 response and significant clinical improvement of the animals. No side effects were observed. Therefore, a potential supportive role for the nutraceutical supplement during canine leishmaniasis is proposed.
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http://dx.doi.org/10.3390/ani9080501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721201PMC
July 2019

Leptin and Immunological Profile in Obesity and Its Associated Diseases in Dogs.

Int J Mol Sci 2019 May 14;20(10). Epub 2019 May 14.

Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy.

Growing scientific evidence has unveiled increased incidences of obesity in domestic animals and its influence on a plethora of associated disorders. Leptin, an adipokine regulating body fat mass, represents a key molecule in obesity, able to modulate immune responses and foster chronic inflammatory response in peripheral tissues. High levels of cytokines and inflammatory markers suggest an association between inflammatory state and obesity in dogs, highlighting the parallelism with humans. Canine obesity is a relevant disease always accompanied with several health conditions such as inflammation, immune-dysregulation, insulin resistance, pancreatitis, orthopaedic disorders, cardiovascular disease, and neoplasia. However, leptin involvement in many disease processes in veterinary medicine is poorly understood. Moreover, hyperleptinemia as well as leptin resistance occur with cardiac dysfunction as a consequence of altered cardiac mitochondrial metabolism in obese dogs. Similarly, leptin dysregulation seems to be involved in the pancreatitis pathophysiology. This review aims to examine literature concerning leptin and immunological status in obese dogs, in particular for the aspects related to obesity-associated diseases.
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http://dx.doi.org/10.3390/ijms20102392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566566PMC
May 2019

Circulating regulatory T cells (Treg), leptin and induction of proinflammatory activity in obese Labrador Retriever dogs.

Vet Immunol Immunopathol 2018 Aug 7;202:122-129. Epub 2018 Jul 7.

Dipartimento di Scienze, Università della Basilicata, Via Nazario Sauro 85, 85100, Potenza, Italy; Dipartimento di Scienze Mediche Traslazionali, Università Federico II, Via Pansini 5, 80131, Napoli, Italy.

Over-nutrition and obesity have been associated with impaired immunity and low-grade inflammation in humans and mouse models. In this context, a causal role for unbalanced T regulatory cell (Treg)-dependent mechanisms has been largely suggested. Obesity is the most common nutritional disorder in dogs. However, it is not defined whether canine obesity may influence circulating Treg as well as if their number variation might be associated with the occurrence of systemic inflammation. The present study investigated the immune profile of healthy adult obese dogs belonging to the Labrador Retriever breed, in comparison with the normal weight counterpart. Indeed, obesity has been described as particularly evident in this dogs. With this purpose, 26 healthy dogs were enrolled and divided into two groups based on body condition score (BCS): controls (CTR: BCS 4-5) and obeses (OB: BCS ≥ 7). Our data indicate that adult obese Labrador Retrievers are characterised by the inverse correlation between leptin serum concentration and circulating Treg (CD4CD25Foxp3) levels. In addition, an increased number of cytotoxic T cell effectors (CD3CD8) and a higher IFN-γ production by cytotoxic T lymphocytes were observed in OB group. These results may provide new insights into the immunological dysregulation frequently associated to obesity in humans and still undefined in dogs.
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http://dx.doi.org/10.1016/j.vetimm.2018.07.004DOI Listing
August 2018

Mechanical phenotyping of K562 cells by the Micropipette Aspiration Technique allows identifying mechanical changes induced by drugs.

Sci Rep 2018 01 19;8(1):1219. Epub 2018 Jan 19.

Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Via G. Campi 213/A, 41125, Modena, Italy.

Mechanical properties of living cells can be used as reliable markers of their state, such as the presence of a pathological state or their differentiation phase. The mechanical behavior of cells depends on the organization of their cytoskeletal network and the main contribution typically comes from the actomyosin contractile system, in both suspended and adherent cells. In the present study, we investigated the effect of a pharmaceutical formulation (OTC - Ossitetraciclina liquida 20%) used as antibiotic, on the mechanical properties of K562 cells by using the Micropipette Aspiration Technique (MAT). This formulation has been shown to increase in a time dependent way the inflammation and toxicity in terms of apoptosis in in vitro experiments on K562 and other types of cells. Here we show that by measuring the mechanical properties of cells exposed to OTC for different incubation times, it is possible to infer modifications induced by the formulation to the actomyosin contractile system. We emphasize that this system is involved in the first stages of the apoptotic process where an increase of the cortical tension leads to the formation of blebs. We discuss the possible relation between the observed mechanical behavior of cells aspirated inside a micropipette and apoptosis.
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http://dx.doi.org/10.1038/s41598-018-19563-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775209PMC
January 2018

Oxytetracycline induces DNA damage and epigenetic changes: a possible risk for human and animal health?

PeerJ 2017 27;5:e3236. Epub 2017 Apr 27.

Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.

Background: Oxytetracycline (OTC), which is largely employed in zootechnical and veterinary practices to ensure wellness of farmed animals, is partially absorbed within the gastrointestinal tract depositing in several tissues. Therefore, the potential OTC toxicity is relevant when considering the putative risk derived by the entry and accumulation of such drug in human and pet food chain supply. Despite scientific literature highlights several OTC-dependent toxic effects on human and animal health, the molecular mechanisms of such toxicity are still poorly understood.

Methods: Here, we evaluated DNA damages and epigenetic alterations by quantitative reverse transcription polymerase chain reaction, quantitative polymerase chain reaction, chromatin immuno-precipitation and Western blot analysis.

Results: We observed that human peripheral blood mononuclear cells (PBMCs) expressed DNA damage features (activation of ATM and p53, phosphorylation of H2AX and modifications of histone H3 methylation of lysine K4 in the chromatin) after the exposure to OTC. These changes are linked to a robust inflammatory response indicated by an increased expression of Interferon (IFN)- and type 1 superoxide dismutase (SOD1).

Discussion: Our data reveal an unexpected biological activity of OTC able to modify DNA and chromatin in cultured human PBMC. In this regard, OTC presence in foods of animal origin could represent a potential risk for both the human and animal health.
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http://dx.doi.org/10.7717/peerj.3236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410137PMC
April 2017

Clinical evaluation of a nutraceutical diet as an adjuvant to pharmacological treatment in dogs affected by Keratoconjunctivitis sicca.

BMC Vet Res 2016 Sep 22;12(1):214. Epub 2016 Sep 22.

Department of Science, University of Basilicata, Via Sauro, 85, 85100, Potenza, Italy.

Background: Canine keratoconjunctivitis sicca (cKCS) is an inflammatory eye condition related to a deficiency in the tear aqueous fraction. Etiopathogenesis of such disease is substantially multifactorial, combining the individual genetic background with environmental factors that contribute to the process of immunological tolerance disruption and, as a consequence, to the emergence of autoimmunity disease. In this occurrence, it is of relevance the role of the physiological immune-dysregulation that results in immune-mediated processes at the basis of cKCS. Current therapies for this ocular disease rely on immunosuppressive treatments. Clinical response to treatment frequently varies from poor to good, depending on the clinical-pathological status of eyes at diagnosis and on individual response to therapy. In the light of the variability of clinical response to therapies, we evaluated the use of an anti-inflammatory/antioxidant nutraceutical diet with potential immune-modulating activity as a therapeutical adjuvant in cKCS pharmacological treatment. Such combination was administered to a cohort of dogs affected by cKCS in which the only immunosuppressive treatment resulted poorly responsive or ineffective in controlling the ocular symptoms.

Results: Fifty dogs of different breeds affected by immune-mediated cKCS were equally distributed and randomly assigned to receive either a standard diet (control, n = 25) or the nutraceutical diet (treatment group, n = 25) both combined with standard immunosuppressive therapy over a 60 days period. An overall significant improvement of all clinical parameters (tear production, conjunctival inflammation, corneal keratinization, corneal pigment density and mucus discharge) and the lack of food-related adverse reactions were observed in the treatment group (p < 0.0001).

Conclusions: Our results showed that the association of traditional immune-suppressive therapy with the antioxidant/anti-inflammatory properties of the nutraceutical diet resulted in a significant amelioration of clinical signs and symptoms in cKCS. The beneficial effects, likely due to the presence of supplemented nutraceuticals in the diet, appeared to specifically reduce the immune-mediated ocular symptoms in those cKCS-affected dogs that were poorly responsive or unresponsive to classical immunosuppressive drugs. These data suggest that metabolic changes could affect the immune response orchestration in a model of immune-mediated ocular disease, as represented by cKCS.
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http://dx.doi.org/10.1186/s12917-016-0841-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034585PMC
September 2016

In Vitro Effects of Some Botanicals with Anti-Inflammatory and Antitoxic Activity.

J Immunol Res 2016 15;2016:5457010. Epub 2016 Aug 15.

Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; Department of Science, University of Basilicata, 85100 Potenza, Italy.

Several extrinsic factors, like drugs and chemicals, can foster autoimmunity. Tetracyclines, in particular oxytetracycline (OTC), appear to correlate with the emergence of immune-mediated diseases. Accumulation of OTC, the elective drug for gastrointestinal and respiratory infectious disease treatment in broiler chickens, was reported in chicken edible tissues and could represent a potential risk for pets and humans that could assume this antibiotic as residue in meat or in meat-derived byproducts. We investigated the in vitro anti-inflammatory properties of a pool of thirteen botanicals as a part of a nutraceutical diet, with proven immunomodulatory activity. In addition, we evaluated the effect of such botanicals in contrasting the in vitro proinflammatory toxicity of OTC. Our results showed a significant reduction in interferon- (INF-) γ production by human and canine lymphocytes in presence of botanicals ((⁎) p < 0.05). Increased INF-γ production, dependent on 24-hour OTC-incubation of T lymphocytes, was significantly reduced by the coincubation with Haematococcus pluvialis, with Glycine max, and with the mix of all botanicals ((⁎) p < 0.05). In conclusion, the use of these botanicals was shown to be able to contrast OTC-toxicity and could represent a new approach for the development of functional foods useful to enhance the standard pharmacological treatment in infections as well as in preventing or reducing the emergence of inflammatory diseases.
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http://dx.doi.org/10.1155/2016/5457010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002466PMC
March 2017

Clinical evaluation of an antiinflammatory and antioxidant diet effect in 30 dogs affected by chronic otitis externa: preliminary results.

Vet Res Commun 2016 Mar 7;40(1):29-38. Epub 2016 Jan 7.

Department of Science, University of Basilicata, Potenza, Italy.

The aim of this evaluation study was to assess the possible role of a specific nutraceutical diet in relieving main clinical symptoms of chronic bilateral otitis externa (occlusion of ear canal, erythema, discharge quantity, and odor) in 30 adult dogs. Thirty dogs of different breeds (mean age ± SEM; 6.03 ± 0.15 years and mean weight ± SEM; 32.01 ± 1.17 Kg; 53.3% males, 46.6% females) with evident chronic clinical otitis symptoms were equally divided and randomly assigned to receive either the nutraceutical diet (ND group) or a standard diet (SD group) over a period of 90 days. In all cases a topical pharmacological treatment was given. The nutraceutical diet, also endowed with anti-inflammatory and antioxidant activities, significantly decreased the mean score intensity of all symptoms after 90 days of intervention (P < 0.0001) with the exception of Malassezia pachydermatis infection which was only slightly reduced. Our investigation is one of the few evidence-based results where a commercial nutraceutical diet has been proven effective, in combination with drugs, in relieving otitis externa-related symptoms. This study opens new insights into otitis externa clinical management providing evidence of efficacy of a combined therapy with drugs and a specific nutraceutical diet.
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http://dx.doi.org/10.1007/s11259-015-9651-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754334PMC
March 2016

An immune-modulating diet increases the regulatory T cells and reduces T helper 1 inflammatory response in Leishmaniosis affected dogs treated with standard therapy.

BMC Vet Res 2015 Dec 3;11:295. Epub 2015 Dec 3.

Department of Translational Medical Sciences, University of Naples Federico II, Via Pansini, 5, 80131, Naples, Italy.

Background: Clinical appearance and evolution of Canine Leishmaniosis (CL) are the consequence of complex interactions between the parasite and the genetic and immunological backgrounds. We investigated the effect of an immune-modulating diet in CL. Dogs were treated with anti- Leishmania pharmacological therapy combined with standard diet (SD Group) or with the immune-modulating diet (IMMD Group). CD3+ CD4+ Foxp3+ Regulatory T cells (Treg) and CD3+ CD4+ IFN-γ + T helper 1 (Th1) were analyzed by flow cytometry.

Results: All sick dogs showed low platelet number at diagnosis (T0). A platelet increase was observed after six months (T6) SD Group, with still remaining in the normal range at twelve months (T12). IMMD Group showed an increase in platelet number becoming similar to healthy dogs at T6 and T12. An increase of CD4/CD8 ratio was revealed in SD Group after three months (T3), while at T6 and at T12 the values resembled to T0. The increase in CD4/CD8 ratio at T3 was maintained at T6 and T12 in IMMD Group. A reduction in the percentage of Treg of all sick dogs was observed at T0. A recovery of Treg percentage was observed only at T3 in SD Group, while this effect disappeared at T6 and T12. In contrast, Treg percentage became similar to healthy animals in IMDD Group at T3, T6 and T12. Sick dogs showed an increase of Th1 cells at T0 as compared with healthy dogs. We observed the occurrence of a decrease of Th1 cells from T3 to T12 in SD Group, although a trend of increase was observed at T6 and T12. At variance, IMMD Group dogs showed a progressive decrease of Th1 cells, whose levels became similar to healthy controls at T6 and T12.

Conclusion: The immune-modulating diet appears to regulate the immune response in CL during the standard pharmacological treatment. The presence of nutraceuticals in the diet correlates with the decrease of Th1 cells and with the increase of Treg in sick dogs. Therefore, the administration of the specific dietary supplement improved the clinical response to the standard treatment in a model of CL.
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http://dx.doi.org/10.1186/s12917-015-0610-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669625PMC
December 2015

Novel STAT1 gain-of-function mutation and suppurative infections.

Pediatr Allergy Immunol 2016 Mar 15;27(2):220-3. Epub 2015 Dec 15.

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

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http://dx.doi.org/10.1111/pai.12496DOI Listing
March 2016

The IFN-β 1b effect on Cu Zn superoxide dismutase (SOD1) in peripheral mononuclear blood cells of relapsing-remitting multiple sclerosis patients and in neuroblastoma SK-N-BE cells.

Brain Res Bull 2015 Sep 3;118:1-6. Epub 2015 Sep 3.

Dipartimento di Medicina Clinica e Chirurgia, Unità di Fisiologia, Università degli Studi di Napoli Federico II, Italy. Electronic address:

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease leading to axonal injury. Even if the etiology of MS is still unknown the disease begins with inflammation involving autoreactive T lymphocytes activation in genetically susceptible subjects. Interferon beta-1b (IFN β 1b) is one of the most used drug in the MS therapy. The results obtained in this study show that the concentration of SOD1 in CSF of relapsing-remitting MS (RR-MS) patients, evaluated by enzyme-linked immunosorbent assay (ELISA), is decreased compared to pathological controls. Moreover, the Western blotting analysis demonstrated that SOD1 in human peripheral blood mononuclear cells (PBMC) in healthy controls was significantly higher compared to MS subjects before starting DMT therapy. In addition IFN β 1b therapy causes an increase of intracellular SOD1 protein as well as mRNA levels in PBMC. Moreover, the treatment of neuroblastoma SK-N-BE cells with IFN β 1b increased SOD1 protein and mRNA levels; these data also suggest that neuroprotective effect of this physiological molecule is, at least in part, carried out through its effect on SOD1. This study demonstrate that DMT therapy is able to increase SOD1 expression in PBMC of RR-MS patients. Therefore, the effectiveness of DMT therapy can be ascribed, at least in part, to an increased levels of this antioxidant enzyme as further confirmed by in vitro studies in SK-N-BE cells.
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http://dx.doi.org/10.1016/j.brainresbull.2015.08.009DOI Listing
September 2015

GRP78 mediates cell growth and invasiveness in endometrial cancer.

J Cell Physiol 2014 Oct;229(10):1417-26

Department of Molecular Medicine and Medical Biotechnologies & Institute of Endocrinology and Molecular Oncology of CNR, University "Federico II", Naples, Italy.

Recent studies have indicated that endoplasmic reticulum stress, the unfolded protein response activation and altered GRP78 expression can play an important role in a variety of tumors development and progression. Very recently we reported for the first time that GRP78 is increased in endometrial tumors. However, whether GRP78 could play a role in the growth and/or invasiveness of endometrial cancer cells is still unknown. Here we report that the silencing of GRP78 expression affects both cell growth and invasiveness of Ishikawa and AN3CA cells, analyzed by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and transwell migration assay, respectively. At variance with Ishikawa cells, AN3CA cells showed, besides an endoplasmic reticulum, also a plasma membrane GRP78 localization, evidenced by both immunofluorescence and cell membrane biotinylation experiments. Intriguingly, flow cytometry experiments showed that the treatment with a specific antibody targeting GRP78 C-terminal domain caused apoptosis in AN3CA but not in Ishikawa cells. Induction of apoptosis in AN3CA cells was not mediated by the p53 pathway activation but was rather associated to reduced AKT phosphorylation. Interestingly, immunofluorescence analysis evidenced that endometrioid adenocarcinoma tissues displayed, similarly to AN3CA cells, also a GRP78 plasma membrane localization. These data suggest that GRP78 and its plasma membrane localization, might play a role in endometrial cancer development and progression and might constitute a novel target for the treatment of endometrial cancer.
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http://dx.doi.org/10.1002/jcp.24578DOI Listing
October 2014

T cell activation induces CuZn superoxide dismutase (SOD)-1 intracellular re-localization, production and secretion.

Biochim Biophys Acta 2014 Feb 31;1843(2):265-74. Epub 2013 Oct 31.

Dipartimento di Scienze Mediche Traslazionali, Università di Napoli "Federico II", 80131 Napoli, Italy. Electronic address:

Reactive oxygen species (ROS) behave as second messengers in signal transduction for a series of receptor/ligand interactions. A major regulatory role is played by hydrogen peroxide (H2O2), more stable and able to freely diffuse through cell membranes. Copper-zinc superoxide dismutase (CuZn-SOD)-1 is a cytosolic enzyme involved in scavenging oxygen radicals to H2O2 and molecular oxygen, thus representing a major cytosolic source of peroxides. Previous studies suggested that superoxide anion and H2O2 generation are involved in T cell receptor (TCR)-dependent signaling. Here, we describe that antigen-dependent activation of human T lymphocytes significantly increased extracellular SOD-1 levels in lymphocyte cultures. This effect was accompanied by the synthesis of SOD-1-specific mRNA and by the induction of microvesicle SOD-1 secretion. It is of note that SOD-1 increased its concentration specifically in T cell population, while no significant changes were observed in the "non-T" cell counterpart. Moreover, confocal microscopy showed that antigen-dependent activation was able to modify SOD-1 intracellular localization in T cells. Indeed, was observed a clear SOD-1 recruitment by TCR clusters. The ROS scavenger N-acetylcysteine (NAC) inhibited this phenomenon. Further studies are needed to define whether SOD-1-dependent superoxide/peroxide balance is relevant for regulation of T cell activation, as well as in the functional cross talk between immune effectors.
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http://dx.doi.org/10.1016/j.bbamcr.2013.10.020DOI Listing
February 2014

Regulatory T cells, Cytotoxic T lymphocytes and a T(H)1 cytokine profile in dogs naturally infected by Leishmania infantum.

Res Vet Sci 2013 Dec 22;95(3):942-9. Epub 2013 Aug 22.

Department of Veterinary Medicine and Animal Productions, Division of Internal Medicine, University of Naples Federico II, Via Delpino, 1, 80137 Naples, Italy.

Canine leishmaniasis caused by the protozoan parasite Leishmania infantum is a chronic systemic disease endemic in Mediterranean basin. The aim of the study is to investigate the immune profile of dogs naturally infected by Leishmania infantum. In order to address such issue, CD4(+) and CD8(+) lymphocyte T cell subsets, peripheral CD4(+)CD3(+)Foxp3(+) (Treg) levels and the presence of pro-inflammatory T cells have been assessed, in 45 infected dogs and in 30 healthy animals, by using immunofluorescence and flow cytometry detection. Animals were categorised according to their clinical-pathological status and their antibody titer at diagnosis. Results showing a significant increase of CD8(+)CD3(+) T lymphocytes, a reduced percentage of the T regulatory CD4(+)CD3(+)Foxp3(+) subset and a significant increase of T(H)1 cells, characterise the infected dogs, regardless of their antibody titer or the occurrence of clinical symptomatic disease. These data may provide new insights into the pathogenesis of immune-mediated alterations associated with canine leishmaniasis.
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http://dx.doi.org/10.1016/j.rvsc.2013.08.005DOI Listing
December 2013

Effects of recombinant trout leptin in superoxide production and NF-κB/MAPK phosphorylation in blood leukocytes.

Peptides 2013 Oct 8;48:59-69. Epub 2013 Aug 8.

Dipartimento di Scienze e Tecnologie, Universita' del Sannio, Italy. Electronic address:

Studies in mammals indicate that leptin is a multifunctional cytokine involved in regulation of energy metabolism and the modulation of the immune function. However, evidence for an immunomodulatory effect of leptin in fish is still missing. At least in part, this lack of knowledge is due to the absence of materials and models. In this study, we produced trout recombinant leptin (rt-lep) and tested its capacity to trigger cellular pathways, usually active in mammal immune system cells. STAT3, NF-κB, and the three major MAPK cascades (JNK, p38 and ERK), were activated by rt-lep in in vitro incubations with blood leucocytes of the rainbow trout Oncorhynchus mykiss. We also showed that rt-lep causes a decrease in superoxide anion production in trout blood leucocytes. Thus our data indicate that as in mammals also in teleosts leptin plays pleiotropic activities. Importantly, its actions in fishes do not always conform to the picture emerging for mammals.
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http://dx.doi.org/10.1016/j.peptides.2013.07.026DOI Listing
October 2013

Natural killer expansion, human leukocyte antigens-E expression and CD14(+) CD56(+) monocytes in a myelodysplastic syndrome patient.

Eur J Haematol 2013 Sep 28;91(3):265-9. Epub 2013 Jun 28.

Department of Science, University of Basilicata, Potenza, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy.

Myelodysplastic syndromes (MDS) are clonal disorders characterized by ineffective hematopoiesis and possible evolution to acute leukemia. Occurrence of stem cell defects and of immune-mediated mechanisms was evidenced as relevant for pathophysiology of MDS. Here, we described one case of MDS patient carrying CD14(+) CD56(+) monocytes in bone marrow (BM), in the presence of a defective human leukocyte antigen (HLA)-E expression on peripheral blood (PB) cells and of natural killer (NK) cell expansion in PB and BM. The defective HLA-E expression and the NK expansion are proposed to be relevant for the pathogenesis of myelodysplasia in those patients showing CD14(+) CD56(+) monocytes in BM.
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http://dx.doi.org/10.1111/ejh.12152DOI Listing
September 2013

NK cells blur the frontier between innate and acquired immunity.

Front Immunol 2012 2;3:400. Epub 2013 Jan 2.

Department of Science, University of Basilicata Potenza, Italy ; Department of Cellular and Molecular Biology and Pathology, University of Naples Federico II Napoli, Italy.

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http://dx.doi.org/10.3389/fimmu.2012.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534153PMC
January 2013

HLA-E and HLA class I molecules on bone marrow and peripheral blood polymorphonuclear cells of myelodysplatic patients.

Leuk Res 2013 Feb 3;37(2):169-74. Epub 2012 Oct 3.

Dipartimento di Scienze, Università della Basilicata, Potenza, Italy.

Relevance of immune-dysregulation for emergence, dominance and progression of dysplastic clones in myelodysplastic syndromes (MDS) was suggested, but valuable or predictive criteria on this involvement are lacking. We previously reported that reduced T-regulatory cells (Treg) and high CD54 expression on T cell identify a sub-group of patients in whom an immune-pathogenesis might be inferred. Here, we suggest the occurrence of immune-selection of dysplastic clones in a subgroup of MDS patients, with reduced HLA-I and HLA-E on PMN, and propose that an altered immune profile might represent a valuable criterion to classify Low/Int-1 patients on the basis of immune-pathogenesis of MDS.
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http://dx.doi.org/10.1016/j.leukres.2012.09.015DOI Listing
February 2013

Eculizumab treatment modifies the immune profile of PNH patients.

Immunobiology 2012 Jul 3;217(7):698-703. Epub 2011 Dec 3.

Department of Biochemistry and Biomedical Technologies, University of Naples Federico II, Italy.

Paroxysmal Nocturnal Haemoglobinuria (PNH) is due to pathological expansion of a stem progenitor bearing a somatic mutation of PIG-A gene involved in the biosynthesis of the glycosyl-phosphatidyl-inositol (GPI) anchor. Numerous data suggest a role for immune-mediated mechanisms in the selection/expansion of GPI-defective clone. Haemolytic anaemia in PNH is dependent on the effect of complement against GPI-defective red cells. Eculizumab, an anti-C5 monoclonal antibody, is dramatically effective in controlling haemolysis and thrombosis, in reducing fatigue and in improving quality of life of patients. However, this therapy presents new challenges that need to be properly faced. Here, we report the decrease in B, Natural Killer (NK) and regulatory T cells (Treg), an altered cytokine profile of invariant-NKT cells (NKTi) and the increasing of C-X-C chemokine receptor type 4 (CXCR4) receptor in PNH patients before the Eculizumab therapy. Treatment significantly affects some of these alterations: after Eculizumab, the number of B lymphocytes, the cytokine secretion of NKTi and CXCR4 expression on CD8 T cells became similar to healthy donors. No effects were observed on NK and Treg. The amplitude of the GPI-defective compartment remained unchanged.
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http://dx.doi.org/10.1016/j.imbio.2011.11.009DOI Listing
July 2012

Endoplasmic reticulum stress is activated in endometrial adenocarcinoma.

Gynecol Oncol 2012 Apr 4;125(1):220-5. Epub 2011 Dec 4.

Department of Obstetrics and Gynecology, University Federico II, Naples, Italy.

Objectives: Endometrial cancer is the most common malignancy of the female genital tract. However, in spite of a huge advance in our understanding of endometrial cancer biology, therapeutic modalities haven't significantly changed over the past 40 years. The activation of the Unfolded Protein Response (UPR) and GRP78 increase following Endoplasmic Reticulum (ER) stress have been recently identified as mechanisms favoring growth, invasion and resistance to therapy of different types of cancer. However, a possible role of ER stress and GRP78 in endometrial cancer has never been investigated.

Methods: Tissue specimens from normal and neoplastic endometrium were analyzed for the expression of the ER stress markers GRP78, ATF6 and CHOP by Real-Time RT-PCR. In addition, GRP78 protein expression and localization were evaluated by Western blot and immunohistochemistry, respectively. The effect of GRP78 knock down on cell growth of Ishikawa cells was analyzed by proliferation curve analysis.

Results: In this analysis, the expression levels of GRP78, ATF6 and CHOP mRNAs were significantly increased in specimens of endometrioid endometrial carcinomas. GRP78 and ATF6 protein expression levels were also increased in specimens of endometrial adenocarcinomas. GRP78 knock down caused a decrease of Ishikawa cells' growth.

Conclusions: The increased expression of ER stress markers in endometrioid endometrial carcinomas suggests a role for ER stress, the UPR and, possibly, GRP78 in endometrial cancer. Whether these mechanisms have a substantial function in the pathogenesis of malignant transformation of human endometrium is still under investigation in our laboratory.
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http://dx.doi.org/10.1016/j.ygyno.2011.11.045DOI Listing
April 2012

Tyr phosphatase-mediated P-ERK inhibition suppresses senescence in EIA + v-raf transformed cells, which, paradoxically, are apoptosis-protected in a MEK-dependent manner.

Neoplasia 2011 Feb;13(2):120-30

Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Facoltà di Scienze Matematiche Fisiche e Naturali, Università degli Studi del Salento, Lecce, Italy.

Activation of the Ras-Raf-extracellular signal-regulated kinase (ERK) pathway causes not only proliferation and suppression of apoptosis but also the antioncogenic response of senescence. How these contrasting effects are reconciled to achieve cell transformation and cancer formation is poorly understood. In a system of two-step carcinogenesis (dedifferentiated PC EIA, transformed PC EIA-polyoma-middle T [PC EIA + Py] and PC EIA-v-raf [PC EIA + raf] cells], v-raf cooperated with EIA by virtue of a strong prosurvival effect, not elicited by Py-middle T, evident toward serum-deprivation-and H(2)O(2)-induced apoptosis. Apoptosis was detected by DNA fragmentation and annexin V staining. The prosurvival function of v-raf was, in part, mitogen-activated protein kinase/ERK kinase (MEK)-dependent, as shown by pharmacological MEK inhibition. The MEK-dependent antiapoptotic effect of v-raf was exerted despite a lower level of P-ERK1/2 in EIA + raf cells with respect to EIA + Py/EIA cells, which was dependent on a high tyrosine phosphatase activity, as shown by orthovanadate blockade. An ERK1/2 tyrosine phosphatase was likely involved. The high tyrosine phosphatase activity was instrumental to the complete suppression of senescence, detected by β-galactosidase activity, because tyrosine phosphatase blockade induced senescence in EIA + raf but not in EIA + Py cells. High tyrosine phosphatase activity and evasion from senescence were confirmed in an anaplastic thyroid cancer cell line. Therefore, besides EIA, EIA + raf cells suppress senescence through a new mechanism, namely, phosphatase-mediated P-ERK1/2 inhibition, but, paradoxically, retain the oncogenic effects of the Raf-ERK pathway. We propose that the survival effect of Raf is not a function of absolute P-ERK1/2 levels at a given time but is rather dynamically dependent on greater variations after an apoptotic stimulus.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033591PMC
http://dx.doi.org/10.1593/neo.101152DOI Listing
February 2011