Publications by authors named "Ilaria Cimmino"

16 Publications

  • Page 1 of 1

Implication of the NLRP3 Inflammasome in Bovine Age-Related Sarcopenia.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

Department of Veterinary Medicine and Animal Production, Unit of Pathology, University of Naples "Federico II", 80137 Naples, Italy.

Sarcopenia is defined as the age-related loss of skeletal muscle mass, quality, and strength. The pathophysiological mechanisms underlying sarcopenia are still not completely understood. The aim of this work was to evaluate, for the first time, the expression of NLRP3 inflammasome in bovine skeletal muscle in order to investigate the hypothesis that inflammasome activation may trigger and sustain a pro-inflammatory environment leading to sarcopenia. Samples of skeletal muscle were collected from 60 cattle belonging to three age-based groups. Morphologic, immunohistochemical and molecular analysis were performed to assess the presence of age-related pathologic changes and chronic inflammation, the expression of NLRP3 inflammasome and to determine the levels of interleukin-1β, interleukin-18 and tumor necrosis factor alpha in muscle tissue. Our results revealed the presence of morphologic sarcopenia hallmark, chronic lymphocytic inflammation and a type II fibers-selective NLRP3 expression associated to a significant decreased number of immunolabeled-fibers in aged animals. Moreover, we found a statistically significant age-related increase of pro-inflammatory cytokines such as interleukin-1β and interleukin-18 suggesting the activation of NLRP3 inflammasome. Taken together, our data suggest that NLRP3 inflammasome components may be normally expressed in skeletal muscle, but its priming and activation during aging may contribute to enhance a pro-inflammatory environment altering normal muscular anabolism and metabolism.
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http://dx.doi.org/10.3390/ijms22073609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036417PMC
March 2021

Urinary Biomarkers in Tumors: An Overview.

Methods Mol Biol 2021 ;2292:3-15

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Recent reports suggest that urine is a useful noninvasive tool for the identification of urogenital tumors, including bladder, prostate, kidney, and other nonurological cancers. As a liquid biopsy, urine represents an important source for the improvement of new promising biomarkers, a suitable tool to identify indolent cancer and avoid overtreatment. Urine is enriched with DNAs, RNAs, proteins, circulating tumor cells, exosomes, and other small molecules which can be detected with several diagnostic methodologies.We provide an overview of the ongoing state of urinary biomarkers underlying both their potential utilities to improve cancer prognosis, diagnosis, and therapeutic strategy and their limitations.
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http://dx.doi.org/10.1007/978-1-0716-1354-2_1DOI Listing
April 2021

Can early switch to rituximab-bendamustine in a patient with follicular non-Hodgkin lymphoma progressing during R-CHOP be considered frontline treatment?: A case report.

Medicine (Baltimore) 2020 Aug;99(33):e21440

Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola.

Rationale: Follicular non-Hodgkin lymphoma (fNHL) is a neoplasm characterized by an indolent course and chemosensitivity, but also by disease recurrence. Bendamustine is often used as frontline treatment or second line. HEADING DIAGNOSIS:: fNHL.

Patient Concerns: A 63-year-old Caucasian male with diagnosis of fNHL lymphoma underwent to cyclophosphamide, doxorubicin, vincristine, and prednisone associated with rituximab chemoimmunotherapy, during which interim reevaluation showed progressive disease and severe toxicity.

Interventions: Early switch to rituximab-bendamustine.

Outcomes: This regimen was well tolerated, patient compliance was optimal, there were no delays in administration and no infectious episodes. An interim reevaluation after 3 courses revealed that the patient was fit, the blood cell count was normal, and lymphadenopathies and nocturnal sweating had completely regressed. Of note, the PET/CT scan did not show fluorodeoxyglucose pathological uptake, clearly confirming disease regression.

Lessons: Early switching to a bendamustine-rituximab-based scheme, even during conventional chemotherapy, decreases toxicity and reduces the risk of treatment interruption or delay, with favorable effects on overall response and prognosis.
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http://dx.doi.org/10.1097/MD.0000000000021440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437798PMC
August 2020

Potential Mechanisms of Bisphenol A (BPA) Contributing to Human Disease.

Int J Mol Sci 2020 Aug 11;21(16). Epub 2020 Aug 11.

Department of Translational Medicine, Federico II University of Naples and URT "Genomic of Diabetes" of Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR), 80131 Naples, Italy.

Bisphenol A (BPA) is an organic synthetic compound serving as a monomer to produce polycarbonate plastic, widely used in the packaging for food and drinks, medical devices, thermal paper, and dental materials. BPA can contaminate food, beverage, air, and soil. It accumulates in several human tissues and organs and is potentially harmful to human health through different molecular mechanisms. Due to its hormone-like properties, BPA may bind to estrogen receptors, thereby affecting both body weight and tumorigenesis. BPA may also affect metabolism and cancer progression, by interacting with GPR30, and may impair male reproductive function, by binding to androgen receptors. Several transcription factors, including PPARγ, C/EBP, Nrf2, HOX, and HAND2, are involved in BPA action on fat and liver homeostasis, the cardiovascular system, and cancer. Finally, epigenetic changes, such as DNA methylation, histones modification, and changes in microRNAs expression contribute to BPA pathological effects. This review aims to provide an extensive and comprehensive analysis of the most recent evidence about the potential mechanisms by which BPA affects human health.
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http://dx.doi.org/10.3390/ijms21165761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460848PMC
August 2020

Diagnosis of Flier's syndrome in a patient with nondiabetic hypoglycemia: a case report and critical appraisal of the literature.

Endocrine 2020 07 9;69(1):73-78. Epub 2020 Apr 9.

Department of Translational Medicine, Federico II University of Naples and URT "Genomic of Diabetes" of Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR), Naples, Italy.

Purpose: Autoimmune hypoglycemia includes rare syndromes characterized by the presence of either anti-insulin antibodies (IAA) (Hirata's disease) or anti-insulin receptor (anti-ISR) antibodies (Flier's syndrome). Diagnosis is usually based on identification of the specific antibodies, in presence of the Whipple triad. However, most of these cases are classified as idiopathic diseases due to the difficulty to define the pathogenic culprit.

Methods: Basic research methodologies, including Western Blot and ELISA tests, have been used in this study.

Results: We describe a 21-year-old young woman (PT), non-obese and non-diabetic, with a positive history of autoimmune diseases, admitted to the hospital for recurrent episodes of severe symptomatic hypoglycemia. Counterregulatory response to hypoglycemia was normal as well as the fasting test, so excluding both hormone deficiencies and insulinoma. Since an autoimmune hypoglycemic syndrome was suspected, the hyperactivation of the insulin pathway was experimentally evaluated. At this purpose, human hepatocarcinoma (HepG2) cells were incubated with serum obtained from the patient (PT) and from control individuals. Interestingly, a significant increase of phosphorylation of insulin receptor, Akt, and ERK1/2 was observed in the HepG2 cells incubated with PT serum compared with the controls. ELISA tests revealed significantly increased levels of anti-ISR antibodies in PT serum, while IAA were similar both in PT and in control sera, supporting diagnosis of Flier's syndrome.

Conclusions: This study emphasizes the importance to identify new strategies for the differential diagnosis of hypoglycemia, not always possible with the routinely used diagnostic tests.
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http://dx.doi.org/10.1007/s12020-020-02287-4DOI Listing
July 2020

Autophagy and NLRP3 inflammasome crosstalk in neuroinflammation in aged bovine brains.

J Cell Physiol 2020 06 5;235(6):5394-5403. Epub 2020 Jan 5.

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

NLRP3 inflammasome is a multiprotein complex that can sense several stimuli such as autophagy dysregulation and increased reactive oxygen species production stimulating inflammation by priming the maturation of proinflammatory cytokines interleukin-1β and interleukin-18 in their active form. In the aging brain, these cytokines can mediate the innate immunity response priming microglial activation. Here, we describe the results of immunohistochemical and molecular analysis carried out on bovine brains. Our results support the hypothesis that the age-related impairment in cellular housekeeping mechanisms and the increased oxidative stress can trigger the inflammatory danger sensor NLRP3. Moreover, according to the recent scientific literature, we demonstrate the presence of an age-related proinflammatory environment in aged brains consisting in an upregulation of interleukin-1β, an increased microglial activation and increased NLRP3 expression. Finally, we suggest that bovine may potentially be a pivotal animal model for brain aging studies.
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http://dx.doi.org/10.1002/jcp.29426DOI Listing
June 2020

Prep1 regulates angiogenesis through a PGC-1α-mediated mechanism.

FASEB J 2019 12 15;33(12):13893-13904. Epub 2019 Oct 15.

Department of Translational Medicine, Research Unit (URT) Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR), University of Naples Federico II, Naples, Italy.

Angiogenesis depends on a delicate balance between the different transcription factors, and their control should be considered necessary for preventing or treating diseases. Pre-B-cell leukemia transcription factor regulating protein 1 (Prep1) is a homeodomain transcription factor that plays a primary role in organogenesis and metabolism. Observations performed in a hypomorphic mouse model, expressing 3-5% of the protein, show an increase of embryonic lethality due, in part, to defects in angiogenesis. In this study, we provide evidence that overexpression of in mouse aortic endothelial cells (MAECs) stimulates migration, proliferation, and tube formation. These effects are paralleled by an increase of several proangiogenic factors and by a decrease of the antiangiogenic gene neurogenic locus notch homolog protein 1 (Notch1). Prep1-mediated angiogenesis involves the activation of the p160 Myb-binding protein (p160)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway. Indeed, overexpression increases its binding with p160 and induces a 4-fold increase of p160 and 70% reduction of PGC-1α compared with control cells. Incubation of MAECs with a synthetic Prep1(54-72) peptide, mimicking the Prep1 region involved in the interaction with p160, reverts the proangiogenic effects mediated by Prep1. In addition, Prep1 levels increase by 3.2-fold during the fibroblast growth factor β (bFGF)-mediated endothelial colony-forming cells' activation, whereas Prep1(54-72) peptide reduces the capability of these cells to generate tubular-like structures in response to bFGF, suggesting a possible role of Prep1 both in angiogenesis from preexisting vessels and in postnatal vasculogenesis. Finally, hypomorphic heterozygous mice, expressing low levels of Prep1, show attenuated placental angiogenesis and vessel formation within Matrigel plugs. All of these observations indicate that Prep1, complexing with p160, decreases PGC-1α and stimulates angiogenesis.-Cimmino, I., Margheri, F., Prisco, F., Perruolo, G., D'Esposito, V., Laurenzana, A., Fibbi, G., Paciello, O., Doti, N., Ruvo, M., Miele, C., Beguinot, F., Formisano, P., Oriente, F. Prep1 regulates angiogenesis through a PGC-1α-mediated mechanism.
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http://dx.doi.org/10.1096/fj.201901230RRDOI Listing
December 2019

Low-dose Bisphenol-A regulates inflammatory cytokines through GPR30 in mammary adipose cells.

J Mol Endocrinol 2019 11;63(4):273-283

Department of Translational Medicine, Federico II University of Naples and URT "Genomic of Diabetes" of Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR), Naples, Italy.

The dramatic rise in obesity and metabolic syndrome can be related, at least in part, to environmental chemical factors such as Bisphenol-A (BPA). In this study, we aimed to understand the effects of low-dose Bisphenol-A on the human mature adipocytes and stromal vascular fraction (SVF) cells, obtained from subcutaneous mammary adipose tissue of overweight female patients, undergoing surgical mammary reduction. 24 and/or 48-h exposure to BPA 0.1 nM elicited significant increase of the inflammatory molecules interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemo-attractant protein 1α (MCP1α) and induced G protein-coupled estrogen receptor 30 (GPR30) levels more than two-fold both in mature adipocytes and SVF cells. These effects were similar to that obtained in the presence of GPR30-specific agonist G1 (100 nM) and were reverted by G15 (1 µM), a GPR30-selective antagonist. As a result of BPA-GPR30 signaling activation, fatty acid synthase (FAS) and leptin mRNA levels were significantly higher upon BPA exposure (P < 0.05) in mature adipocytes, with an opposite effect on adiponectin (ADIPOQ). In addition, an increase in SVF cell proliferation and ERK1/2 phosphorylation, was observed, compared to untreated cells. G15 reverted all of these effects. Interestingly, the action of BPA on SVF cell growth was mimicked by IL-8 treatment and was reverted by incubation with anti-IL8 antibodies. All these data suggest that BPA at 0.1 nM, a ten times lower concentration than environmental exposure, increases the expression of pro-inflammatory cytokines via GPR30 both in mature mammary adipocytes and in SVF cells with a possible involvement of IL-8.
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http://dx.doi.org/10.1530/JME-18-0265DOI Listing
November 2019

The Relevance of Insulin Action in the Dopaminergic System.

Front Neurosci 2019 16;13:868. Epub 2019 Aug 16.

Department of Translational Medicine, University of Naples Federico II, Naples, Italy.

The advances in medicine, together with lifestyle modifications, led to a rising life expectancy. Unfortunately, however, aging is accompanied by an alarming boost of age-associated chronic pathologies, including neurodegenerative and metabolic diseases. Interestingly, a non-negligible interplay between alterations of glucose homeostasis and brain dysfunction has clearly emerged. In particular, epidemiological studies have pointed out a possible association between Type 2 Diabetes (T2D) and Parkinson's Disease (PD). Insulin resistance, one of the major hallmark for etiology of T2D, has a detrimental influence on PD, negatively affecting PD phenotype, accelerating its progression and worsening cognitive impairment. This review aims to provide an exhaustive analysis of the most recent evidences supporting the key role of insulin resistance in PD pathogenesis. It will focus on the relevance of insulin in the brain, working as pro-survival neurotrophic factor and as a master regulator of neuronal mitochondrial function and oxidative stress. Insulin action as a modulator of dopamine signaling and of alpha-synuclein degradation will be described in details, too. The intriguing idea that shared deregulated pathogenic pathways represent a link between PD and insulin resistance has clinical and therapeutic implications. Thus, ongoing studies about the promising healing potential of common antidiabetic drugs such as metformin, exenatide, DPP IV inhibitors, thiazolidinediones and bromocriptine, will be summarized and the rationale for their use to decelerate neurodegeneration will be critically assessed.
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http://dx.doi.org/10.3389/fnins.2019.00868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706784PMC
August 2019

Prep1, A Homeodomain Transcription Factor Involved in Glucose and Lipid Metabolism.

Front Endocrinol (Lausanne) 2018 28;9:346. Epub 2018 Jun 28.

Department of Translational Medicine, Federico II University of Naples, Naples, Italy.

The three-amino acid loop extension (TALE) homeodomain proteins are a family of transcription factor including the mammalian Pbx, MEIS and Prep proteins. TALE proteins can bind other transcription factors such as Pdx-1 and play an important role in the regulation of glucose metabolism. Experiments performed in mutant mice have shown that while the single or knockout mice feature pancreatic islet malformations, impaired glucose tolerance and hypoinsulinemia, the trans-heterozygous mice develop age-dependent overt diabetes mellitus. In contrast, Prep1 plays a different role with respect to these proteins. Indeed, hypomorphic mice, expressing low levels of protein, feature pancreatic islet hypoplasia accompanied by hypoinsulinemia similar to Pbx1 or Pdx1. Nevertheless, these animals show increased insulin sensitivity in skeletal muscle, liver and adipose tissue accompanied by protection from streptozotocin-induced diabetes. In addition, hypomorphic mice feature reduced triglyceride synthesis and do not develop steatohepatitis after a methionine and coline deficient diet. In this review we have underlined how important metabolic functions are controlled by TALE proteins, in particular by Prep1, leading to hypothesis that its suppression might represent beneficial effect in the care of metabolic diseases.
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http://dx.doi.org/10.3389/fendo.2018.00346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032887PMC
June 2018

Prep1 deficiency improves metabolic response in white adipose tissue.

Biochim Biophys Acta Mol Cell Biol Lipids 2018 May 21;1863(5):515-525. Epub 2018 Feb 21.

Department of Translational Medicine, Federico II University of Naples and URT "Genomic of Diabetes" of Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR), Naples, Italy. Electronic address:

Prep1 is a gene encoding for a homeodomain transcription factor which induces hepatic and muscular insulin resistance. In this study, we show that Prep1 hypomorphic heterozygous (Prep1) mice, expressing low levels of protein, featured a 23% and a 25% reduction of total body lipid content and epididymal fat, respectively. The percentage of the small adipocytes (25-75 μm) was 30% higher in Prep1 animals than in the WT, with a reciprocal difference in the large adipose cells (100-150 and >150 μm). Insulin-stimulated insulin receptor tyrosine and Akt serine phosphorylation markedly increased in Prep1 mice, paralleled by 3-fold higher glucose uptake and a significant increase of proadipogenic genes such as C/EBPα, GLUT4, and FABP4. Moreover, T cells infiltration and TNF-α, IFNγ and leptin expression were reduced in adipose tissue from Prep1 mice, while adiponectin levels were 2-fold higher. Furthermore, Prep1 mature adipocytes released lower amounts of pro-inflammatory cytokines and higher amount of adiponectin compared to WT cells. Incubation of murine liver cell line (NMuLi) with conditioned media (CM) from mature adipocytes of Prep1 mice improved glucose metabolism, while those from WT mice had no effect. Consistent with these data, Prep1 overexpression in 3T3-L1 adipocytes impaired adipogenesis and insulin signaling, and increased proinflammatory cytokine secretion. All these findings suggest that Prep1 silencing reduces inflammatory response and increases insulin sensitivity in adipose tissue. In addition, CM from mature adipocytes of Prep1 mice improve metabolism in hepatic cells.
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http://dx.doi.org/10.1016/j.bbalip.2018.02.005DOI Listing
May 2018

Prep1 Deficiency Affects Olfactory Perception and Feeding Behavior by Impairing BDNF-TrkB Mediated Neurotrophic Signaling.

Mol Neurobiol 2018 Aug 18;55(8):6801-6815. Epub 2018 Jan 18.

Department of Translational Medical Science, "Federico II" University of Naples and URT "Genomics of Diabetes", Institute of Experimental Endocrinology and Oncology of CNR, Via Pansini 5, 80131, Naples, Italy.

Prep1 is a homeodomain transcription factor which has an important role in hindbrain development. Prep1 expression is also kept in adult mouse brain and in particular within the olfactory bulbs. Moreover, many Prep1 neurons co-localize with Calbindin-positive periglomerular interneurons in olfactory glomerular layer. However, Prep1 function in this brain region is still unknown. In this study, we show that Prep1 hypomorphic heterozygous (Prep1) mice express low levels of protein and feature a 30% reduction of olfactory bulb area, compared to WT mice. In addition, Prep1 mice olfactory bulb histological analysis indicated a 20% lower cytochrome C oxidase activity within the glomerular layer, accompanied by a reduced number of periglomerular interneurons, compared to the WT littermates. Consistently, olfactory perception test highlighted that Prep1 hypomorphic heterozygous mice display a scant ability to distinguish odors, which significantly impacts on feeding behavior, as Prep1 mice revealed a reduced preference for high-fat food. Analysis of BDNF signaling, which represents the main molecular mediator of olfactory plasticity, showed that Prep1 mouse olfactory bulbs feature a 30% reduction of TrkB receptor levels and a decreased activation of ERK1/2. Similarly, overexpression of Prep1 in mouse neuronal cells (N2A) caused an increase of TrkB expression levels, BDNF-induced ERK phosphorylation, and cell viability, compared to control cells. We conclude that Prep1 deficiency alters olfactory morpho-functional integrity and olfaction-mediated eating behavior by affecting BDNF-TrkB signaling. Prep1 could, therefore, play a crucial role in behavioral dysfunctions associated to impaired responsiveness to BDNF.
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http://dx.doi.org/10.1007/s12035-018-0873-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061220PMC
August 2018

A peptide antagonist of Prep1-p160 interaction improves ceramide-induced insulin resistance in skeletal muscle cells.

Oncotarget 2017 Sep 30;8(42):71845-71858. Epub 2017 May 30.

Department of Translational Medicine, Federico II University of Naples and URT "Genomic of Diabetes" of Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR), Naples, Italy.

Prep1 is a homeodomain transcription factor belonging to the TALE protein family. Its overexpression affects glucose metabolism in several tissues. In particular, in skeletal muscle tissue the interaction of Prep1 with its cofactor p160 impairs GLUT4 expression and glucose uptake. In this study, we show that ceramides (C2cer), a class of lipids antagonizing insulin signalling, increase the levels of Prep1 and p160 in a dose and time-dependent fashion in L6 cells and induce their association by 80%. We find that C2cer exposure inhibits insulin receptor, IRS1 and Akt phosphorylation and reduces insulin-stimulated glycogen content and glucose uptake by 1.3- and 2.1-fold, respectively. The synthetic Prep1(54-72) peptide, mimicking the Prep1 region involved in the interaction with p160, reduces Prep1-p160 binding in a dose-dependent way (IC = 0.20μM). In C2cer-treated L6 cells, 10μM Prep1(54-72) restores insulin signalling impaired by ceramide treatment. Prep1 overexpressing L6 cells display similar metabolic alterations observed in ceramide-treated L6 cells and the presence of Prep1(54-72) mitigates these events. All these findings suggest that disruption of the Prep1/p160 molecular interaction enhances insulin sensitivity impaired by ceramides in skeletal muscle cells and indicate this complex as an important target for type 2 diabetes.
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http://dx.doi.org/10.18632/oncotarget.18286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641094PMC
September 2017

Secondary syphilis mimicking malignancy: A case report and review of literature.

J Infect Chemother 2017 Aug 26;23(8):576-578. Epub 2017 Apr 26.

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

A 56-year-old man developed disseminate lymphadenopathies, associated with hepato-splenomegaly, fever, nocturnal sweating and weight loss. Imaging studies in particular FDG-PET/CT raised the suspicion of a malignant disease. But blood flow cytometry assay for B/T cell clonality was negative and fine-needle biopsy of enlarged laterocervical lymph node showed a not specific "reactive hyperplasia". Four months later, the patient developed a non-itching rash; since a further anamnestic investigation revealed an history of high-risk sexual intercourse, the patient underwent serological tests for Treponema pallidum that were positive at high titer, after a first negative screening. Made the diagnosis of secondary syphilis, the patient responded to the treatment with benzyl penicillin with complete resolution of symptoms. This case highlights the importance of carefully screening the patients with suspected lymphoadenopathies also for lue, particularly in presence of behavioral risk factors.
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http://dx.doi.org/10.1016/j.jiac.2017.03.003DOI Listing
August 2017

Human Peripheral Blood Mononuclear Cell Function and Dendritic Cell Differentiation Are Affected by Bisphenol-A Exposure.

PLoS One 2016 10;11(8):e0161122. Epub 2016 Aug 10.

Department of Translational Medical Sciences, Federico II University of Naples, via S. Pansini 5-80131, Naples, Italy.

Environmental pollutants, including endocrine disruptor chemicals (EDCs), interfere on human health, leading to hormonal, immune and metabolic perturbations. Bisphenol-A (BPA), a main component of polycarbonate plastics, has been receiving increased attention due to its worldwide distribution with a large exposure. In humans, BPA, for its estrogenic activity, may have a role in autoimmunity, inflammatory and allergic diseases. To this aim, we assessed the effect of low BPA doses on functionality of human peripheral blood mononuclear cells (PBMCs), and on in vitro differentiation of dendritic cells from monocytes (mDCs). Fresh peripheral blood samples were obtained from 12 healthy adult volunteers. PBMCs were left unstimulated or were activated with the mitogen phytohemagglutinin (PHA) or the anti-CD3 and anti-CD28 antibodies and incubated in presence or absence of BPA at 0.1 and 1nM concentrations. The immune-modulatory effect of BPA was assessed by evaluating the cell proliferation and the levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-10 (IL-10) and interleukin-13 (IL-13) secreted by PBMCs. mDCs were differentiated with IL-4 and GC-CSF with or without BPA and the expression of differentiation/maturation markers (CD11c, CD1a, CD86, HLA-DR) was evaluated by flow cytometry; furthermore, a panel of 27 different cytokines, growth factors and chemokines were assayed in the mDC culture supernatants. PBMCs proliferation significantly increased upon BPA exposure compared to BPA untreated cells. In addition, a significant decrease in IL-10 secretion was observed in PBMCs incubated with BPA, either in unstimulated or mitogen-stimulated cells, and at both 0.1 and 1nM BPA concentrations. Similarly, IL-13 was reduced, mainly in cells activated by antiCD3/CD28. By contrast, no significant changes in IFN-γ and IL-4 production were found in any condition assayed. Finally, BPA at 1nM increased the density of dendritic cells expressing CD1a and concomitantly decreased the expression of HLA-DR and CD86 activation markers. In conclusion, in humans the exposure to BPA causes on PBMCs a significant modulation of proliferative capacity and cytokine production, and on mDCs alteration in differentiation and phenotype. These immune cell alterations suggest that low dose chronic exposure to BPA could be involved in immune deregulation and possibly in the increased susceptibility to develop inflammatory and autoimmune diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161122PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980038PMC
August 2017

Low-Dose Bisphenol-A Impairs Adipogenesis and Generates Dysfunctional 3T3-L1 Adipocytes.

PLoS One 2016 4;11(3):e0150762. Epub 2016 Mar 4.

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

Environmental endocrine disruptors (EDCs), including bisphenol-A (BPA), have been recently involved in obesity and diabetes by dysregulating adipose tissue function. Our aim was to examine whether prolonged exposure to low doses of BPA could affect adipogenesis and adipocyte metabolic functions. Therefore, 3T3-L1 pre-adipocytes were cultured for three weeks with BPA 1 nM to mimic human environmental exposure. We evaluated BPA effect on cell proliferation, differentiation, gene expression and adipocyte metabolic function. BPA significantly increased pre-adipocyte proliferation (p<0.01). In 3T3-L1 adipocytes differentiated in the presence of BPA, the expression of Peroxisome proliferator-activated receptor gamma (PPARγ), Fatty Acid Binding Protein 4/Adipocyte Protein 2 (FABP4/AP2) and CCAAT/enhancer binding protein (C/EBPα) was increased by 3.5, 1.5 and 3 folds, respectively. Mature adipocytes also showed a significant increase in lipid accumulation (p<0.05) and alterations of insulin action, with significant reduction in insulin-stimulated glucose utilization (p<0.001). Moreover, in mature adipocytes, mRNA levels of Leptin, interleukin-6 (IL6) and interferon-γ (IFNγ) were significantly increased (p<0.05). In conclusion, BPA prolonged exposure at low doses, consistent with those found in the environment, may affect adipocyte differentiation program, enhancing pre-adipocyte proliferation and anticipating the expression of the master genes involved in lipid/glucose metabolism. The resulting adipocytes are hypertrophic, with impaired insulin signaling, reduced glucose utilization and increased pro-inflammatory cytokine expression. Thus, these data supported the hypothesis that BPA exposure, during critical stages of adipose tissue development, may cause adipocyte metabolic dysfunction and inflammation, thereby increasing the risk of developing obesity-related diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150762PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778877PMC
July 2016