Emanuela Corsini - Academia.edu (original) (raw)

Papers by Emanuela Corsini

Toxicology and Applied Pharmacology, 2019

Allergic contact dermatitis (ACD) is caused by topical exposure to chemical allergens. Keratinocy... more Allergic contact dermatitis (ACD) is caused by topical exposure to chemical allergens. Keratinocytes play a key role in innate immunity, as well as in ACD progression. The transmembrane Toll-like receptor 4 (TLR4), strongly implicated in skin inflammation, has the ability to bind Damage Associated Molecular Patterns (DAMPs), like Low Molecular Weight Hyaluronan (LMWHA). Previously, we had determined that p-phenylenediamine (PPD) and 2,4-dinitrochlorobenzene (DNCB) modulate keratinocyte HA deposition in a manner correlated to their sensitization. In the present study, we aimed to investigate putative cooperation of HA and TLR4 in the process of PPD and DNCB-induced keratinocyte activation. Contact sensitizers were shown to significantly increase the expression of Hyaluronan Synthases (HAS) and TLR4 in NCTC2544 human keratinocytes, as demonstrated by western blot and Real-Time PCR. These data, in correlation to earlier shown enhanced HA degradation suggest that the contact sensitizers facilitate HA turnover of keratinocytes and increase the release of pro-inflammatory, LMWHA fragments. Treatment with exogenous LMWHA enhanced TLR4, HAS levels and Nuclear factor-kappa beta (NF-κΒ) activation. PPD, DNCB and LMWHA-effects were shown to be partly executed through TLR4 downstream signaling as shown by Real-Time, western blot, siRNA and confocal microscopy approaches. Specifically, PPD and DNCB stimulated the activation of the TLR4 downstream mediator NF-κB. Therefore, the shown upregulation of TLR4 expression is suggested to further facilitate the release of endogenous, bioactive HA fragments and sustain keratinocyte activation. In conclusion, keratinocyte contact allergen-dependent sensitization is partly mediated through a LMWHA/TLR4/ NF-κB signaling axis.

Frontiers in Immunology

Glyphosate (G) is the active ingredient of the most used herbicides worldwide. Its use is current... more Glyphosate (G) is the active ingredient of the most used herbicides worldwide. Its use is currently very debated, as several studies indicating its hazard and toxicity are emerging. Among them, there is evidence of adverse effects on the immune system. The aim of this work was to investigate if G could directly affect immune cells. Peripheral blood mononuclear cells (PBMC) obtained from healthy donors were used as experimental model. PBMC were expose to G and stimulated with PMA/ionomycin, T helper (Th) cell differentiation and cytokine production were assessed by flow cytometry and enzyme-linked immunosorbent assay, respectively. A reduction of Th1/Th2 ratio, mainly due to a decrease in Th1 cells, was observed following G exposure. Results show an enhancement of IL-4 and IL-17A production, and a reduction of IFN-γ. Based on literature evidence that suggest G being an endocrine disruptor, we investigated the role of nuclear estrogen receptors (ER). ERα/ERβ inhibition by ICI 182,780 ...

Frontiers in Toxicology, 2021

Endocrine disruptors (ED) are natural and anthropogenic chemicals that can interfere with hormona... more Endocrine disruptors (ED) are natural and anthropogenic chemicals that can interfere with hormonal systems at different levels. As such, ED-induced alterations in hormone functions have been implicated in many diseases and pathological conditions, including adverse developmental, reproductive, neurological, cardiovascular, and immunological effects in mammals. The fact that ED may compete with several endogenous hormones for multiple receptors and pathways is not always fully considered. This results in a complex response that depends on the cellular context in terms of receptors and interacting proteins and, thus, may differ between tissues and circumstances. Microglia, neurons, and other immune cells are potential targets and still underappreciated actors in endocrine disruption. Due to the large scale of this topic, this review is not intended to provide a comprehensive review nor a systematic review of chemicals identified as endocrine disruptors. It focuses on the immune-neuro-...

Cells, 2021

Cancer is one of the most common causes of death worldwide, and its development is a result of th... more Cancer is one of the most common causes of death worldwide, and its development is a result of the complex interaction of genetic factors, environmental cues, and aging. Hormone-sensitive cancers depend on the action of one or more hormones for their development and progression. Sex steroids and corticosteroids can regulate different physiological functions, including metabolism, growth, and proliferation, through their interaction with specific nuclear receptors, that can transcriptionally regulate target genes via their genomic actions. Therefore, interference with hormones’ activities, e.g., deregulation of their production and downstream pathways or the exposition to exogenous hormone-active substances such as endocrine-disrupting chemicals (EDCs), can affect the regulation of their correlated pathways and trigger the neoplastic transformation. Although nuclear receptors account for most hormone-related biologic effects and their slow genomic responses are well-studied, less-kno...

Frontiers in Pharmacology, 2021

Receptor for activated C kinase 1 (RACK1) has an important role in immune activation, and is regu... more Receptor for activated C kinase 1 (RACK1) has an important role in immune activation, and is regulated through a balance between glucocorticoid and androgen levels. We have previously demonstrated that RACK1 expression can serve as a marker for evaluation of immunotoxic profiles of hormone-active substances, such as endocrine-disrupting chemicals (EDCs). In this study, we investigated the effects of three bisphenols (BPA, BPAF, BPS) on RACK1 expression and on the innate immune responses in the THP-1 human promyelocytic cell line, a validated model for this investigation. BPA and BPAF reduced RACK1 promoter transcriptional activity, mRNA expression, and protein levels. However, BPS had the opposite effect. As expected, these results on RACK1 were paralleled by lipopolysaccharide (LPS)-induced interleukin-8 (IL-8) and tumor necrosis factor-α (TNFα) production. Since BPA and BPAF induced RACK1 expression in the presence of glucocorticoid receptor (GR) antagonist mifepristone, a role of...

Oncogenesis, 2020

Recent data indicate that receptor for activated C kinase 1 (RACK1) is a putative prognostic mark... more Recent data indicate that receptor for activated C kinase 1 (RACK1) is a putative prognostic marker and drug target in breast cancer (BC). High RACK1 expression is negatively associated with overall survival, as it seems to promote BC progression. In tumors, RACK1 expression is controlled by a complex balance between glucocorticoids and androgens. Given the fact that androgens and androgenic derivatives can inhibit BC cell proliferation and migration, the role of androgen signaling in regulating RACK1 transcription in mammary tumors is of pivotal interest. Here, we provide evidence that nandrolone (19-nortosterone) inhibits BC cell proliferation and migration by antagonizing the PI3K/Akt/NF-κB signaling pathway, which eventually results in RACK1 downregulation. We also show that nandrolone impairs the PI3K/Akt/NF-κB signaling pathway and decreases RACK1 expression via binding to the membrane-bound receptor, oxoeicosanoid receptor 1 (OXER1). High levels of OXER1 are observed in sever...

Frontiers in Pharmacology, 2020

thus indicating that the attenuation of cytokine secretion cannot be directly ascribed to the act... more thus indicating that the attenuation of cytokine secretion cannot be directly ascribed to the activation of Nrf2 signaling pathway. Moreover, all compounds, with the exception of compound 1, attenuated the LPS-induced activation of the NF-kB pathway, by reducing the upstream phosphorylation of IkB, the NF-kB nuclear translocation, as well as the activation of NF-kB promoter. In human PBMCs, compound 4 and CURC attenuated TNFa release as observed in THP-1 cells, and all compounds acting as Nrf2 inducers significantly decreased the levels of MCP-1/CCL2, as well as the release of the proinflammatory cytokine IL-12. Altogether, the compounds induced a differential modulation of innate immune cytokine release, by differently regulating Nrf2 and NF-kB intracellular signaling pathways.

Toxicology in Vitro, 2020

Turkish Journal of Pharmaceutical Sciences, 2019

Objectives: MicroRNAs (miRNAs) are short, endogenous noncoding RNA molecules that can bind to par... more Objectives: MicroRNAs (miRNAs) are short, endogenous noncoding RNA molecules that can bind to parts of target mRNAs, thereby regulating gene expression. Few studies have shown that microRNAs can be up or down-regulated in allergic skin conditions but still, there is a need for further studies. The aim of this study was to investigate the expression of miRNAs in response to the common contact allergen Bandrowski's base (BB), the principal allergen in patients reacting to pphenylenediamine (PPD). Materials and Methods: The human promyelocytic cell line (THP-1) was exposed to BB at the concentration of 1 µg/ml for 24, 48 and 72 hours. The dose was selected from the results of cytotoxicity assays. RNA was purified, and miRNA expression profile and real-time polymerase chain reaction (RT-PCR) were performed to identify up or down-regulated miRNAs and after, to confirm their modulation. Results: Among the different modulated miRNAs, the up-regulation of miRNA-155 and the down-regulation of miRNA-21 were found to be important because these are related to immune systems. This expression profile of miRNAs was also confirmed by RT-PCR. u n c o r r e c t e d p r o o f Conclusion: These preliminary results showed that miR-155 and miR-21 may have a role in the pathogenesis of allergic contact dermatitis. But further studies are needed to clarify their roles.

Toxicology Letters, 2019

Highlights  the extreme allergen DNCB more rapidly activate the NLRP3 inflammasome  NLRP12 conf... more Highlights  the extreme allergen DNCB more rapidly activate the NLRP3 inflammasome  NLRP12 confines NLRP3 in the nucleus  the protein ASC is recruited to the inflammasome after exposure to contact allergens  central role of NF-B in contact allergen-induced Blimp-1 expression ABSTRACT We previously demonstrated that based on their potency, contact allergens differently modulate Blimp-1/NLRP12 expression in human keratinocytes, with the extreme allergen 2,4-dinitrochlorobenzene (DNCB) more rapidly upregulating Blimp-1, leading to downregulation of NLRP12, and to the production of interleukin-18 (IL-18). NCTC2544 was used for all experiments. Dose and time course experiments were performed to evaluate the effect of the selected contact allergens on the parameters investigated. Results indicate, that consistent with previous finding, DNCB more rapidly (3 h) induces NLRP3, ASC protein expression and caspase-1 activation compared to PPD. Immunoprecipitation studies show the recruitment of ASC to the inflammasome following exposure to both allergens, while high level of NLRP12 and less ASC protein were found associated in control cells. By immunohistochemistry, we found increased NLRP3 expression following exposure to contact allergens, and observed a nuclear co-localization of the two proteins, indicating the NLRP12 likely acts preventing the cytosolic localization of NLRP3 and inflammasome assembly. Finally, contact allergen-induced Blimp-1 mRNA and protein expression can be completely blocked by inhibiting NF-B activation, confirming the central role of NF-B in contact allergen-induced keratinocyte activation.

The Science of the total environment, Jan 25, 2017

This work is part of the TOBICUP (TOxicity of BIomass Combustion generated Ultrafine Particles) p... more This work is part of the TOBICUP (TOxicity of BIomass Combustion generated Ultrafine Particles) project which aimed at providing the composition of ultrafine particles (UFPs, i.e. particles with aerodynamic diameter, dae, lower than 100nm) emitted by wood combustion and elucidating the related toxicity. Results here reported are from two ambient monitoring campaigns carried out at an alpine town in Northern Italy, where wood burning is largely diffused for domestic heating in winter. Wintertime and summertime UFP samples were analyzed to assess their chemical composition (i.e. elements, ions, total carbon, anhydrosugars, and polycyclic aromatic hydrocarbons) and biological activity. The induction of the pro-inflammatory cytokine interleukin-8 (IL-8) by UFPs was investigated in two human cells lines (A549 and THP-1) and in human peripheral blood leukocytes. In addition, UFP-induced oxidative stress and genotoxicity were investigated in A549 cells. Ambient UFP-related effects were com...

Toxicology Letters, 2017

Wood-generated UFP Acknowledgments. This project was funded by Fondazione Cariplo (Project TOBICU... more Wood-generated UFP Acknowledgments. This project was funded by Fondazione Cariplo (Project TOBICUP-Ref. 2013-1040). We thank Gruppo Piazzetta (Casella d'Asolo, Italy) for providing pellet and wood stoves.

Toxicology and Applied Pharmacology, 2012

We have previously shown that PFOA and PFOS directly suppress cytokine secretion in immune cells,... more We have previously shown that PFOA and PFOS directly suppress cytokine secretion in immune cells, with different mechanisms of action. In particular, we have demonstrated a role for PPAR-α in PFOA-induced immunotoxicity, and that PFOS has an inhibitory effect on LPS-induced I-κB degradation. These studies investigate the immunomodulatory effects of four other PFCs, namely PFBS, PFOSA, PFDA, and fluorotelomer using in vitro assays. The release of the pro-inflammatory cytokines IL-6 and TNF-α was evaluated in lipolysaccharide (LPS)-stimulated human peripheral blood leukocytes (hPBL) and in the human promyelocytic cell line THP-1, while the release of IL-10 and IFN-γ was evaluated in phytohemagglutinin (PHA)-stimulated hPBL. All PFCs suppressed LPS-induced TNF-α production in hPBL and THP-1 cells, while IL-6 production was suppressed by PFOSA, PFOS, PFDA and fluorotelomer. PFBS, PFOSA, PFOS, PFDA and fluorotelomer inhibited PHA-induced IL-10 release, while IFN-γ secretion was affected by PFOSA, PFOS, PFDA and fluorotelomer. Leukocytes obtained from female donors appear to be more sensitive to the in vitro immunotoxic effects of PFCs when their responses are compared to the results obtained using leukocytes from male donors. Mechanistic investigations demonstrated that inhibition of TNF-α release in THP-1 cells occurred at the transcriptional level. All PFCs, including PFOA and PFOS, decreased LPS-induced NF-κB activation. With the exception of PFOA, none of the PFCs tested was able to activate PPARα driven transcription in transiently transfected THP-1 cells, excluding a role for PPARα in the immunomodulation observed. PFBS and PFDA prevented LPS-induced I-κB degradation. Overall, these studies suggest that PFCs affect NF-κB activation, which directly suppresses cytokine secretion by immune cells. Our results indicate that PFOA is the least active of the PFCs examined followed by PFBS, PFDA, PFOS, PFOSA and fluorotelomer.

Journal of neurochemistry, 2005

Erythropoietin, the principal regulator of erythroids progenitor cells, also promotes neuronal su... more Erythropoietin, the principal regulator of erythroids progenitor cells, also promotes neuronal survival. Using primary cultures of rat hippocampal neurons, we investigated whether erythropoietin could mediate neuroprotection favouring the transcription of brain-derived neurotrophic factor (BDNF). Erythropoietin 2.7 nm reduced by approximately 50% the neuronal death triggered by the prototypic neurotoxicant trimethyltin (TMT) and time-dependently induced BDNF mRNA. This effect resulted in an increased production of biologically active BDNF, which led to a sustained activation of the specific BDNF receptor tyrosine kinase B (TrkB). Reduction of TMT-induced neuronal death by erythropoietin was specifically prevented by a neutralizing anti-BDNF antibody (15 microg/mL), indicating the involvement of this neurotrophin in erythropoietin neuroprotective effect. Intracerebroventricular administration of erythropoietin in mice significantly increases BDNF mRNA expression in brain, supporting ...

Archives of Toxicology, 2011

We previously demonstrated in the human promyelocytic cell line THP-1 that all allergens tested, ... more We previously demonstrated in the human promyelocytic cell line THP-1 that all allergens tested, with the exception of the prohapten isoeugenol, induced a dose-related release of interleukin-8 (IL-8). In the present study, we investigated whether this abnormal behavior was regulated by the AU-rich element-binding proteins HuR and tristetraprolin (TTP) or by the downstream molecule suppressor of cytokine signaling (SOCS)-3. The contact allergens isoeugenol, diethylmaleate (DEM), and 2,4-dinitrochlorobenzene (DNCB), and the irritant salicylic acid were used as reference compounds. Chemicals were used at concentrations that induced a 20% decrease in cell viability as assessed by propidium iodide staining, namely 100 μg/ml (0.61 mM) for isoeugenol, 100 μg/ml (0.58 mM) for DEM, 3 μg/ml (14.8 μM) for DNCB, and 250 μg/ml (1.81 mM) for salicylic acid. Time course experiments of IL-8 mRNA expression and assessment of IL-8 mRNA half-life, indicated a decreased IL-8 mRNA stability in isoeugenol-treated cells. We could demonstrate that a combination and regulation of HuR and TTP following exposure to contact allergens resulted in a different modulation of IL-8 mRNA half-life and release. The increased expression of TTP in THP-1 cells treated with isoeugenol results in destabilization of the IL-8 mRNA, which can account for the lack of IL-8 release. In contrast, the strong allergen DNCB failing to up-regulate TTP, while inducing HuR, resulted in longer IL-8 mRNA half-life and protein release. SOCS-3 was induced only in isoeugenol-treated cells; however, its modulation did not rescue the lack of IL-8 release, indicating that it is unlikely to be involved in the lack of IL-8 production. Finally, the destabilization effect of isoeugenol on IL-8 mRNA expression together with SOCS-3 expression resulted in an anti-inflammatory effect, as demonstrated by the ability of isoeugenol to modulate LPS or ionomycin-induced cytokine release.

Archives of Toxicology, 2020

Fine 2. Author names: Please confirm if the author names are presented accurately and in the corr... more Fine 2. Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 7 Given name: [Marija Sollner] Last name [Dolenc]. Also, kindly confirm the details in the metadata are correct. The given name is Marija, the last name is Sollner Dolenc.

Archives of Toxicology, Jun 17, 2023

EFSA supporting publications, Nov 1, 2019

Prior to being applied to the new bisphenol A (BPA) re-evaluation, the study appraisal methodolog... more Prior to being applied to the new bisphenol A (BPA) re-evaluation, the study appraisal methodology described in the 2017 BPA hazard assessment protocol, i.e. the so-called '2017 methodology', was tested on a selection of studies that had been previously appraised by EFSA in the context of its 2015 and 2016 assessments of BPA. This report describes this testing phase, its outcome and the resulting refinement of the 2017 methodology. The goals of this testing phase were to i) test the functioning of the 2017 internal validity appraisal tools for human and animal studies, and specifically (a) to verify whether the final tier of internal validity (on a three-tier scale, with Tier 1 being the highest) automatically assigned to each study on the basis of pre-defined criteria after answering the questions of the risk of bias tool reflected the internal validity according to expert judgement and (b) to fine-tune and calibrate the 2017 appraisal tool on a sufficiently large study sample (development of the '2019 methodology'); ii) assess the comparability of the study appraisal outcome by the 2019 methodology against the '2015 methodology' applied in the EFSA BPA assessments of 2015 and 2016. Concerning the first goal, the automatic allocation of epidemiological studies to an internal validity tier, based on pre-defined criteria for combining the appraisal questions' scores, resulted in ranking them exclusively in Tier 3 (the lowest tier), in full accordance with expert judgment. For animal studies, to enable discrimination of studies into three tiers, the appraisal tool was refined; thereafter, comparability between automatic allocation-based and expert judgement-based scoring reached 91% (43 out of 47 appraisals). Concerning the second goal, it is acknowledged that the 2015 and 2019 methodologies present some differences with respect to the elements considered for assessing the study quality (i.e. reliability vs. internal validity). Nonetheless, the key study used to derive BPA's tolerable daily intake in the 2015 Opinion was also considered to be of high quality according to the 2019 methodology. In addition, the outcome of the appraisal of the papers by the 2019 methodology versus the 2015 methodology was overall comparable or more stringent in 92% of the cases (24 out of 26 appraisals). It follows that despite some intrinsic differences, the 2015 methodology previously used by EFSA to appraise the BPA evidence is considered sufficiently robust, even though not as structured as the 2019 methodology. Overall, the two goals of the testing phase have been achieved. The amendments of the appraisal methodology are being implemented for the full re-evaluation of the new BPA literature and will be fully documented in the final version of the protocol annexed to the new BPA Opinion.

Zenodo (CERN European Organization for Nuclear Research), Apr 19, 2023

In 2015 you published an opinion setting out a new temporary Tolerable Daily Intake (t-TDI) for B... more In 2015 you published an opinion setting out a new temporary Tolerable Daily Intake (t-TDI) for BPA. Recently you received a request for the re-evaluation of this TDI from the Dutch authorities. Following the new temporary TDI and pending the outcome of the discussions following the Dutch request, the Commission plans to hold a vote on a draft Commission Regulation in the Standing Committee on Plants, Animals, Food and Feed. This draft Regulation would lower the specific migration limit for BPA from plastic food contact materials and would apply the same limit to food contact varnishes and coatings.