Marco Lucarelli
@uniroma1.it
Dept. of Experimental Medicine
Sapienza University of Rome
RESEARCH INTERESTS
Regulation of DNA methylation and demethylation processes in eukaryotic cells;
DNA methylation, modulation of gene expression and cell differentiation;
Molecular mechanisms of the gene therapy by small fragment homologous replacement (SFHR);
Molecular genetics of cystic fibrosis and of CFTR-related disorders, as well as study of the genotype/phenotype relationship in this diseases;
Functional characterization of CFTR (cystic fibrosis transmembrane conductance regulator) and ENaC (epithelial sodium channel) genes in physiologic and pathologic conditions;
Molecular diagnostic methodologies and pathogenetic mechanisms underlying cystic fibrosis, CFTR-related disorders, atherosclerosis, alcohol addiction and neurological disorders;
Setup and automation of mutational search methodologies.
Scopus Publications
Scopus Publications
F. Fanfarillo, Brunella Caronti, Marco Lucarelli, Silvia Francati, Luigi Tarani, Mauro Ceccanti, M. Piccioni, L. Verdone, M. Caserta, Sabrina Venditti,et al.
Alcohol consumption has been consistently linked to an increased risk of several cancers, including breast and ovarian cancer. Despite substantial evidence supporting this association, the precise mechanisms underlying alcohol’s contribution to cancer pathogenesis remain incompletely understood. This narrative review focuses on the key current literature on the biological pathways through which alcohol may influence the development of breast and ovarian cancer. Key mechanisms discussed include the modulation of estrogen levels, the generation of reactive oxygen species, the production of acetaldehyde, the promotion of chronic inflammation, and the induction of epigenetic changes. Alcohol’s impact on estrogenic signaling, particularly in the regulation of estrogen and progesterone, is explored in the context of hormone-dependent cancers. Additionally, the role of alcohol-induced DNA damage, mutagenesis, and immune system modulation in tumor initiation and progression is examined. Overall, this review emphasizes the importance of alcohol as a modifiable risk factor for breast and ovarian cancer and highlights the need for further research to clarify its role in cancer biology.
Ginevra Micangeli, Roberto Paparella, Michela Menghi, M. Ceccanti, Giovanna Coriale, Daniela Fiorentino, H. E. Hoyme, M. Fiore, Giampiero Ferraguti, G. Corsello,et al.
Riassunto. Il disturbo dello spettro feto-alcolico (FASD) riunisce sotto la sua definizione un quadro eterogeneo di patologie accomunate dalla comune eziopatogenesi: l'esposizione fetale all'alcol. Nonostante ricerche approfondite, la soglia tossica non è stata ancora definita, obbligando alla raccomandazione di una completa astinenza dall'alcol durante la gravidanza e l'allattamento. La FASD pone anche sfide diagnostiche a causa della sua presentazione clinica varia e del fenotipo eterogeneo. Di conseguenza, non esiste una singola linea guida diagnostica, ma molteplici linee guida, disponibili a livello globale, redatte in base alle competenze prevalenti degli estensori. Questa revisione mira a sintetizzare le linee guida più utilizzate che consentono la diagnosi di FASD. Sebbene siano stati compiuti notevoli sforzi per sintetizzare le linee guida più recenti, non ne esiste ancora una che racchiuda tutti i criteri contenuti nelle precedenti, pertanto la diagnosi contiene ancora elementi di discrezionalità del medico che la pone. In Italia, le linee guida proposte da Hoyme et al., riviste nel 2016, sono comunemente utilizzate, ma l'analisi comparativa tra le linee guida offre preziosi spunti sul loro contesto storico e sull'utilità diagnostica, ponendo le basi per un'ulteriore proposta che le riassuma tutte. Questo lavoro esplora sia le somiglianze che le differenze tra le varie linee guida esistenti, facendo luce sulla loro evoluzione e applicazione pratica.
Michela Menghi, Ginevra Micangeli, Roberto Paparella, M. Ceccanti, Giovanna Coriale, Giampiero Ferraguti, M. Fiore, Daniela Fiorentino, M. Piccioni and Luigi Tarani
Riassunto. Il disturbo dello spettro feto-alcolico (FASD) è una condizione che si verifica quando una persona è esposta all'alcol durante la gravidanza. Le principali manifestazioni cliniche includono anomalie craniofacciali, ritardo della crescita, difetti alla nascita e cambiamenti nella struttura e nella funzione del cervello. Queste alterazioni possono causare deficit nelle capacità cognitive, nella funzione esecutiva, nella memoria, nella vista, nell'udito, nelle capacità motorie, nel comportamento e nell'adattamento sociale. Gli effetti dell'alcol si estendono oltre il cervello, influenzando altri sistemi tra cui organi sensoriali, cuore e reni. Dato che la diagnosi di FASD implica l'esclusione di altre condizioni, i medici devono avere familiarità con le sue caratteristiche principali per facilitare l'identificazione precoce e implementare strategie sanitarie appropriate per la paziente. Inoltre, c'è un'urgente necessità di strategie di prevenzione primaria incentrate sulla sensibilizzazione sui rischi associati al consumo di alcol durante la gravidanza. Gli articoli estratti in questa rassegna mirano ad analizzare e valutare studi incentrati sulle caratteristiche cliniche osservate nei bambini con la FASD; sono stati reperiti da database online come Medline, Medline Complete e PubMed, che coprono la letteratura pubblicata in lingua inglese tra il 1981 e il 2024, utilizzando termini di ricerca come disturbi dello spettro feto-alcolico, sindrome feto-alcolica, esposizione prenatale all'alcol e difetti alla nascita correlati all'alcol. I dati sottolineano che l'esposizione prenatale all'alcol colpisce principalmente il cervello e le sue funzioni, con conseguenti gravi impatti. Inoltre, si osservano frequentemente anomalie in altri organi vitali come i sistemi sensoriale, cardiovascolare e renale.
Ginevra Micangeli, Michela Menghi, Roberto Paparella, M. Ceccanti, Giovanna Coriale, Daniela Fiorentino, Giampiero Ferraguti, M. Fiore and Luigi Tarani
Riassunto. I disturbi dello spettro feto-alcolico (FASD) comprendono una serie di manifestazioni cliniche derivanti dal consumo di alcol da parte della madre durante la gravidanza. Questa condizione si presenta con diverse anomalie, tra cui ritardo della crescita intrauterina ed extrauterina, anomalie fenotipiche, anomalie strutturali cerebrali, ritardi cognitivi e anomalie comportamentali. Purtroppo, la FASD rimane una condizione irreversibile ed epigenetica, con l'astensione totale dall'alcol durante la gravidanza come unica misura preventiva efficace a causa dell'assenza di una terapia praticabile. La diagnosi avviene in genere nel periodo postnatale, in base a una combinazione di anamnesi di esposizione all'alcol e alla presenza delle suddette anomalie fisiche o comportamentali. La diagnosi non è sempre facile da fare anche nel periodo postnatale a causa dei diversi sottotipi di FASD esistenti. Infatti, solo alcuni di questi sottotipi causano anomalie comportamentali o neuroevolutive in assenza di anomalie fisiche patognomoniche. Sebbene i criteri diagnostici siano utili, sfortunatamente, esiste un'eterogeneità derivante dalle diverse linee guida utilizzate nei diversi Paesi. Lo scopo della nostra revisione, basata su una ricerca bibliografica di banche dati online tra cui Medline, Medline Complete, PubMed e Google Scholar, è quindi quello di fornire una panoramica dei criteri diagnostici utilizzati in Italia.
Giampiero Ferraguti, Francesca Fanfarillo, Simona Nicotera, Sergio Terracina, Clementina Moschella, Alessandro Mattia, Maria Chiara David, S. Pichini, Giovanna Coriale, Daniela Fiorentino,et al.
Riassunto. Il disturbo dello spettro feto-alcolico (FASD) è un termine onnicomprensivo utilizzato per descrivere una serie di disturbi causati dal consumo di alcol durante la gestazione. Gli effetti dannosi si manifestano principalmente nel sistema nervoso centrale, nella crescita e nelle caratteristiche facciali distintive. Dato che non esistono trattamenti noti per il FASD, lo screening meticoloso per questa condizione nelle prime fasi della gravidanza ha un significato immenso, limitando le gravi conseguenze derivanti dall'esposizione all'alcol in utero. Le misure di screening per la FASD comprendono la valutazione dei biomarcatori dell'alcol come il fosfatidiletanolo (PEth) nel flusso sanguigno materno, gli esteri etilici degli acidi grassi (FAEE) nel meconio e l'etilglucuronide (EtG) nel meconio, nelle urine materne e nei capelli. In particolare, l'EtG urinario è altamente sensibile e potrebbe essere utilizzato di routine nelle donne in gravidanza per rilevare anche il consumo occasionale. Sono inoltre disponibili valutazioni tramite questionari tra cui AUDIT-C, T-ACE e TWEAK, insieme a un diario alimentare per identificare l'abuso di alcol e le gravidanze ad alto rischio. Tuttavia, questi questionari potrebbero fornire un quadro inadeguato del consumo di alcol nelle donne a causa della loro inclinazione a mentire per conformarsi alle aspettative socioculturali prevalenti. Pertanto, questo lavoro evidenzia l'indispensabile integrazione del rilevamento dei biomarcatori dell'alcol nel corso del monitoraggio della gravidanza, poiché costituisce uno strumento prezioso per facilitare la scoperta precoce di un eventuale FASD.
Giampiero Ferraguti, Silvia Francati, Claudia Codazzo, Giovanna Blaconà, Giancarlo Testino, Antonio Angeloni, Marco Fiore, Mauro Ceccanti, and Marco Lucarelli
MDPI AG
Genetic features of alcohol dependence have been extensively investigated in recent years. A large body of studies has underlined the important role of genetic variants not only in metabolic pathways but also in the neurobiology of alcohol dependence, mediated by the neuronal circuits regulating reward and craving. Serotonin transporter (5-HTT), encoded by the SLC6A4 gene (Solute carrier family 6-neurotransmitter transporter-member 4), is targeted by antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) and plays a pivotal role in serotoninergic transmission; it has been associated with psychiatric diseases and alcohol dependence. Transcriptional regulation and expression of 5-HTT depend not only on epigenetic modifications, among which DNA methylation (CpG and non-CpG) is primarily involved, but also on sequence variations occurring in intron/exon regions and in untranslated regions in 5′ and 3′, being the first sequences important for the splicing machinery and the last for the binding of transcription factors and micro RNAs. This work intends to shed light on the role of sequence variations known to affect the expression or function of 5-HTT in alcohol-dependent individuals. We found a statistically significant difference in the allelic (p = 0.0083) and genotypic (p = 0.0151) frequencies of the tri-allelic polymorphism, with higher function alleles and genotypes more represented in the control population. Furthermore, we identified three haplotypes more frequent in subjects with AUD (p < 0.0001) and one more frequent in the control population (p < 0.0001). The results obtained for the tri-allelic polymorphism in alcohol dependence confirm what is already present in part of the literature. The role of haplotypes requires further studies to be clarified.
Stefania Simonetti, Silvia Lanciotti, Dominga Carlomagno, Flaminia De Cristofaro, Gioacchino Galardo, Bruno Cirillo, Fabio Fiore, Giacomo Bonito, Carola Severi, Paolo Ricci,et al.
Springer Science and Business Media LLC
Abstract Purpose The aim of the study is to identify CT findings that are predictive of recurrence of acute uncomplicated colonic diverticulitis, to better risk-stratify these patients for whom guidelines recommend a conservative outpatient treatment and to determine the appropriate management with an improvement of health costs. Materials and Methods Over the past year, 33 patients enrolled in an outpatient integrated care pathway (PDTA) for uncomplicated acute diverticulitis with 1-year follow-up period, without recurrence, and 33 patients referred to Emergency Department for a recurrent acute diverticulitis were included. Images of admission CT were reviewed by two radiologists and the imaging features were analyzed and compared with Chi-square and Student t tests. Univariate and multivariate Cox regression models were employed to identify parameters that significantly predicted recurrence in 1-year follow-up period and establish cutoff and recurrence-free rates. The maximally selected rank statistics (MSRS) were used to identify the optimal wall thickening cutoff for the prediction of recurrence. Results Patients with recurrence showed a greater mean parietal thickness compared to the group without recurrence (16 mm vs. 11.5 mm; HR 1.25, p < 0.001) and more evidence of grade 4 of peridiverticular inflammation (40% vs. 12%, p = 0.009, HR 3.44). 12-month recurrence-free rates progressively decrease with increasing thickness and inflammation. In multivariate analysis, only parietal thickness maintained its predictive power with an optimal cutpoint > 15 mm that causes a sixfold increased risk of recurrence (HR 6.22; 95% CI, 3.05–12.67; p < 0.001). Beyond thickness and peridiverticular inflammation, predictive value of early recurrence within 90 days from the 1st episode resulted also an Hinchey Ib on admission CT. Conclusions The maximum wall thickening and the grade of peridiverticular inflammation can be considered as predictive factors of recurrence and may be helpful in selecting patients for a tailored treatment to prevent the risk of recurrence.
Marco Occhiuto, Jessica Pepe, Luciano Colangelo, Marco Lucarelli, Antonio Angeloni, Luciano Nieddu, Viviana De Martino, Salvatore Minisola, and Cristiana Cipriani
MDPI AG
Background: We assessed the long-term (24 months) efficacy and safety of monthly calcifediol (0.266 mg) in the correction and maintenance of total 25(OH)D levels in postmenopausal women with basal values <30 ng/mL. Methods: We initially enrolled 45 consecutive patients during the period September 2019–September 2020. After an initial visit, patients were instructed to return at 3, 6, 9, 12 and 24 months for measuring serum total 25(OH)D, ionised calcium, creatinine and isoenzyme of alkaline phosphatase (bALP). Here, we report only the per-protocol analysis, because the COVID-19 pandemic precluded adherence to the scheduled visits for some patients. Results: The patients’ mean age was 62.4 ± 9.0 years. Mean basal 25(OH)D levels were 20.5 ± 5.3 ng/mL. There was a continuous increase of mean 25(OH)D values (p for trend < 0.001). However, mean values at month 24 (36.7 ± 15.9) were not significantly different in respect to values at month 12 (41.2 ± 11.18). At 24 months, only 1 out 19 patients had a value <20 ng/mL. There was a significant decrease with time of mean values of bALP (p < 0.0216), with no significant changes between 12 and 24 months. No significant changes were observed as far as ionised calcium or creatinine were concerned. Conclusions: The long-term administration of calcifediol maintains stable and sustained 25(OH)D concentrations, with no safety concerns.
Eqrem Rusi, Fiorenza Pennacchia, Wael Abu Ruqa, Maria Antonella Zingaropoli, Patrizia Pasculli, Giuseppina Talarico, Giuseppe Bruno, Christian Barbato, Antonio Minni, Luigi Tarani,et al.
MDPI AG
Background: SARS-CoV-2 is the coronavirus responsible for the COVID-19 pandemic. Even though we are no longer in a pandemic situation, people are still getting infected, some of them need hospitalization and a few of them die. Methods: We conducted a retrospective study including 445 patients who accessed the Emergency Section of Policlinico Umberto I, Rome, Italy, where they had routine blood exams. In this study, we focused on the complete blood count, serum creatinine and azotemia. The data were analyzed using ANOVA, Spearman correlation and ROC analyses. They were divided into four groups based on their clinical outcomes: (1) the emergency group (patients who had mild forms and were quickly discharged); (2) the hospital ward group (patients who were admitted to the emergency section and were then hospitalized in a COVID-19 ward); (3) the intensive care unit (ICU) group (patients who required intensive assistance after the admission in the emergency section); (4) the deceased group (patients who had a fatal outcome after admission to the emergency section). Results: We found significant changes for creatinine, azotemia, hematocrit, mean corpuscular hemoglobin concentration, basophils, monocytes, red blood cell distribution width, hemoglobin, hematocrit and red blood cell numbers using ANOVA according to their clinical outcomes, particularly for the deceased group. Also, we found linear correlations of clinical outcomes with eosinophils, hemoglobin, hematocrit, mean corpuscular hemoglobin concentration, lymphocyte, neutrophil, platelet and red blood cell number and red blood cell distribution width. Conclusions: This study discloses an early association between “classical” routine blood biomarkers and the severity of clinical outcomes in Omicron patients.
Sergio Terracina, Luigi Tarani, Mauro Ceccanti, Mario Vitali, Silvia Francati, Marco Lucarelli, Sabrina Venditti, Loredana Verdone, Giampiero Ferraguti, and Marco Fiore
MDPI AG
Fetal alcohol spectrum disorders (FASD) represent a continuum of lifelong impairments resulting from prenatal exposure to alcohol, with significant global impact. The “spectrum” of disorders includes a continuum of physical, cognitive, behavioral, and developmental impairments which can have profound and lasting effects on individuals throughout their lives, impacting their health, social interactions, psychological well-being, and every aspect of their lives. This narrative paper explores the intricate relationship between oxidative stress and epigenetics in FASD pathogenesis and its therapeutic implications. Oxidative stress, induced by alcohol metabolism, disrupts cellular components, particularly in the vulnerable fetal brain, leading to aberrant development. Furthermore, oxidative stress is implicated in epigenetic changes, including alterations in DNA methylation, histone modifications, and microRNA expression, which influence gene regulation in FASD patients. Moreover, mitochondrial dysfunction and neuroinflammation contribute to epigenetic changes associated with FASD. Understanding these mechanisms holds promise for targeted therapeutic interventions. This includes antioxidant supplementation and lifestyle modifications to mitigate FASD-related impairments. While preclinical studies show promise, further clinical trials are needed to validate these interventions’ efficacy in improving clinical outcomes for individuals affected by FASD. This comprehensive understanding of the role of oxidative stress in epigenetics in FASD underscores the importance of multidisciplinary approaches for diagnosis, management, and prevention strategies. Continued research in this field is crucial for advancing our knowledge and developing effective interventions to address this significant public health concern.
Giampiero Ferraguti, Sergio Terracina, Luigi Tarani, Francesca Fanfarillo, Sara Allushi, Brunella Caronti, Paola Tirassa, Antonella Polimeni, Marco Lucarelli, Luca Cavalcanti,et al.
MDPI AG
Nerve growth factor (NGF) plays a dual role both in inflammatory states and cancer, acting both as a pro-inflammatory and oncogenic factor and as an anti-inflammatory and pro-apoptotic mediator in a context-dependent way based on the signaling networks and its interaction with diverse cellular components within the microenvironment. This report aims to provide a summary and subsequent review of the literature on the role of NGF in regulating the inflammatory microenvironment and tumor cell growth, survival, and death. The role of NGF in inflammation and tumorigenesis as a component of the inflammatory system, its interaction with the various components of the respective microenvironments, its ability to cause epigenetic changes, and its role in the treatment of cancer have been highlighted in this paper.
Roberto Paparella, Giampiero Ferraguti, Marco Fiore, Michela Menghi, Ginevra Micangeli, Francesca Tarani, Aurora Ligotino, Marisa Patrizia Messina, Mauro Ceccanti, Antonio Minni,et al.
MDPI AG
Klinefelter syndrome (KS) is a male genetic disease caused by the presence of an extra X chromosome, causing endocrine disorders mainly responsible for a high rate of infertility and metabolic disorders in adulthood. Scientific research is interested in identifying new biomarkers that can be predictive or prognostic of alterations strictly connected to KS. Lipocalin-2 (LCN-2, also known as NGAL) is a small protein initially identified within neutrophils as a protein related to innate immunity. Serum LCN-2 estimation seems to be a useful tool in predicting the metabolic complications caused by several pathological conditions. However, little is known about its potential role in infertility conditions. The present pilot study aims to investigate the presence of LCN-2 in the serum of a group of pre-pubertal and post-pubertal children affected by KS, compared to healthy controls. We demonstrated for the first time the presence of elevated levels of LCN-2 in the serum of KS patients, compared to controls. This increase was accompanied, in pre-pubertal KS patients, by the loss of correlation with LH and HDL, which instead was present in the healthy individuals. Moreover, in all KS individuals, a positive correlation between LCN-2 and inhibin B serum concentration was found. Despite the limited size of the sample analyzed, our preliminary data encourage further studies to confirm the findings and to extend the study to KS adult patients, to verify the predictive/prognostic value of LCN-2 as new biomarker for metabolic diseases and infertility associated with the pathology.
Francesca Fanfarillo, Giampiero Ferraguti, Marco Lucarelli, Andrea Fuso, Mauro Ceccanti, Sergio Terracina, Ginevra Micangeli, Luigi Tarani, and Marco Fiore
Bentham Science Publishers Ltd.
: Alcohol use disorders are responsible for 5.9% of all death annually and 5.1% of the global disease burden. It has been suggested that alcohol abuse can modify gene expression through epigenetic processes, namely DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol influence on epigenetic mechanisms leads to molecular adaptation of a wide number of brain circuits, including the hypothalamus-hypophysis-adrenal axis, the prefrontal cortex, the mesolimbic-dopamine pathways and the endogenous opioid pathways. Epigenetic regulation represents an important level of alcohol-induced molecular adaptation in the brain. It has been demonstrated that acute and chronic alcohol exposure can induce opposite modifications in epigenetic mechanisms: acute alcohol exposure increases histone acetylation, decreases histone methylation and inhibits DNA methyltransferase activity, while chronic alcohol exposure induces hypermethylation of DNA. Some studies investigated the chromatin status during the withdrawal period and the craving period and showed that craving was associated with low methylation status, while the withdrawal period was associated with elevated activity of histone deacetylase and decreased histone acetylation. Given the effects exerted by ethanol consumption on epigenetic mechanisms, chromatin structure modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, might represent a new potential strategy to treat alcohol use disorder. Further investigations on molecular modifications induced by ethanol might be helpful to develop new therapies for alcoholism and drug addiction targeting epigenetic processes.
Francesca Fanfarillo, Giampiero Ferraguti, Marco Lucarelli, Silvia Francati, Christian Barbato, Antonio Minni, Mauro Ceccanti, Luigi Tarani, Carla Petrella, and Marco Fiore
Bentham Science Publishers Ltd.
Abstract: Reactive oxygen species (ROS) are highly reactive molecules derived from molecular oxygen (O2). ROS sources can be endogenous, such as cellular organelles and inflammatory cells, or exogenous, such as ionizing radiation, alcohol, food, tobacco, chemotherapeutical agents and infectious agents. Oxidative stress results in damage of several cellular structures (lipids, proteins, lipoproteins, and DNA) and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging. A large body of studies showed that ROS plays an important role in carcinogenesis. Indeed, increased production of ROS causes accumulation in DNA damage leading to tumorigenesis. Various investigations demonstrated the involvement of ROS in gliomagenesis. The most common type of primary intracranial tumor in adults is represented by glioma. Furthermore, there is growing attention on the role of the Nerve Growth Factor (NGF) in brain tumor pathogenesis. NGF is a growth factor belonging to the family of neurotrophins. It is involved in neuronal differentiation, proliferation and survival. Studies were conducted to investigate NGF pathogenesis's role as a pro- or anti-tumoral factor in brain tumors. It has been observed that NGF can induce both differentiation and proliferation in cells. The involvement of NGF in the pathogenesis of brain tumors leads to the hypothesis of a possible implication of NGF in new therapeutic strategies. Recent studies have focused on the role of neurotrophin receptors as potential targets in glioma therapy. This review provides an updated overview of the role of ROS and NGF in gliomagenesis and their emerging role in glioma treatment.
Michela Orticello, Rosaria A. Cavallaro, Daniele Antinori, Tiziana Raia, Marco Lucarelli, and Andrea Fuso
MDPI AG
Besides its role in coagulation, vitamin K seems to be involved in various other mechanisms, including inflammation and age-related diseases, also at the level of gene expression. This work examined the roles of two vitamin K2 (menaquinones) vitamers, namely, menaquinone-4 (MK4) and reduced menaquinone-7 (MK7R), as gene modulator compounds, as well as their potential role in the epigenetic regulation of genes involved in amyloidogenesis and neuroinflammation. The SK-N-BE human neuroblastoma cells provided a “first-line” model for screening the neuroinflammatory and neurodegenerative molecular pathways. MK7R, being a new vitamin K form, was first tested in terms of solubilization, uptake and cell viability, together with MK4 as an endogenous control. We assessed the expression of key factors in amyloidogenesis and neuroinflammation, observing that the MK7R treatment was associated with the downregulation of neurodegeneration- (PSEN1 and BACE1) and neuroinflammation- (IL-1β and IL-6) associated genes, whereas genes retaining protective roles toward amiloidogenesis were upregulated (ADAM10 and ADAM17). By profiling the DNA methylation patterns of genes known to be epigenetically regulated, we observed a correlation between hypermethylation and the downregulation of PSEN1, IL-1β and IL-6. These results suggest a possible role of MK7R in the treatment of cognitive impairment, giving a possible base for further preclinical experiments in animal models of neurodegenerative disease.
Stefania Lo Cicero, Germana Castelli, Giovanna Blaconà, Sabina Maria Bruno, Giovanni Sette, Riccardo Pigliucci, Valeria Rachela Villella, Speranza Esposito, Immacolata Zollo, Francesca Spadaro,et al.
Springer Science and Business Media LLC
Stefania Lo Cicero, Germana Castelli, Giovanna Blaconà, Sabina Maria Bruno, Giovanni Sette, Riccardo Pigliucci, Valeria Rachela Villella, Speranza Esposito, Immacolata Zollo, Francesca Spadaro,et al.
Springer Science and Business Media LLC
AbstractCystic fibrosis (CF) is caused by defects of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR-modulating drugs may overcome specific defects, such as the case of Trikafta, which is a clinically approved triple combination of Elexacaftor, Tezacaftor and Ivacaftor (ETI) that exhibited a strong ability to rescue the function of the most frequent F508del pathogenic variant even in genotypes with the mutated allele in single copy. Nevertheless, most rare genotypes lacking the F508del allele are still not eligible for targeted therapies. Via the innovative approach of using nasal conditionally reprogrammed cell (CRC) cell-based models that mimic patient disease in vitro, which are obtainable from each patient due to the 100% efficiency of the cell culture establishment, we theratyped orphan CFTR mutation L1077P. Protein studies, Forskolin-induced organoid swelling, and Ussing chamber assays congruently proved the L1077P variant function rescue by ETI. Notably, this rescue takes place even in the context of a single-copy L1077P allele, which appears to enhance its expression. Thus, the possibility of single-allele treatment also arises for rare genotypes, with an allele-specific modulation as part of the mechanism. Of note, besides providing indication of drug efficacy with respect to specific CFTR pathogenic variants or genotypes, this approach allows the evaluation of the response of single-patient cells within their genetic background. In this view, our studies support in vitro guided personalized CF therapies also for rare patients who are nearly excluded from clinical trials.
Karina Kleinfelder, Virginia Lotti, Adriana Eramo, Felice Amato, Stefania Lo Cicero, Germana Castelli, Francesca Spadaro, Alessia Farinazzo, Daniele Dell’Orco, Sara Preato,et al.
Elsevier BV
Sergio Terracina, Giampiero Ferraguti, Luigi Tarani, Francesca Fanfarillo, Paola Tirassa, Massimo Ralli, Giannicola Iannella, Antonella Polimeni, Marco Lucarelli, Antonio Greco,et al.
MDPI AG
NGF plays a crucial immunomodulatory role and increased levels are found in numerous tissues during autoimmune states. NGF directly modulates innate and adaptive immune responses of B and T cells and causes the release of neuropeptides and neurotransmitters controlling the immune system activation in inflamed tissues. Evidence suggests that NGF is involved in the pathogenesis of numerous immune diseases including autoimmune thyroiditis, chronic arthritis, multiple sclerosis, systemic lupus erythematosus, mastocytosis, and chronic granulomatous disease. Furthermore, as NGF levels have been linked to disease severity, it could be considered an optimal early biomarker to identify therapeutic approach efficacy. In conclusion, by gaining insights into how these molecules function and which cells they interact with, future studies can devise targeted therapies to address various neurological, immunological, and other disorders more effectively. This knowledge may pave the way for innovative treatments based on NGF manipulation aimed at improving the quality of life for individuals affected by diseases involving neurotrophins.
Sabina Maria Bruno, Giovanna Blaconà, Stefania Lo Cicero, Germana Castelli, Mariarita Virgulti, Giancarlo Testino, Silvia Pierandrei, Andrea Fuso, Giuseppe Cimino, Giampiero Ferraguti,et al.
MDPI AG
In the precision medicine era of cystic fibrosis (CF), therapeutic interventions, by the so-called modulators, target the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The levels of targetable CFTR proteins are a main variable in the success of patient-specific therapy. In turn, the CFTR protein level depends, at least in part, on the level of CFTR mRNA. Many mechanisms can modulate the CFTR mRNA level, for example, transcriptional rate, stability of the mRNA, epigenetics, and pathogenic variants that can affect mRNA production and degradation. Independently from the causes of variable CFTR mRNA levels, their exact quantitative assessment is of great importance in CF. Methods with high analytical sensitivity, precision, and accuracy are mandatory for the quantitative evaluation aimed at the amelioration of the diagnostic, prognostic, and therapeutic aspects. This paper compares, for the first time, two CFTR gene expression quantification methods: a well-established method for the relative quantification of CFTR mRNA using a real-time PCR and an innovative method for its absolute quantification using a droplet digital PCR. No comprehensive methods for absolute CFTR quantification via droplet digital PCR have been published so far. The accurate quantification of CFTR expression at the mRNA level is a critical step for the personalized therapeutic approaches of CF.
Tiziana Raia, Federica Armeli, Rosaria A. Cavallaro, Giampiero Ferraguti, Rita Businaro, Marco Lucarelli, and Andrea Fuso
MDPI AG
DNA methylation, the main epigenetic modification regulating gene expression, plays a role in the pathophysiology of neurodegeneration. Previous evidence indicates that 5′-flanking hypomethylation of PSEN1, a gene involved in the amyloidogenic pathway in Alzheimer’s disease (AD), boosts the AD-like phenotype in transgenic TgCRND8 mice. Supplementation with S-adenosylmethionine (SAM), the methyl donor in the DNA methylation reactions, reverts the pathological phenotype. Several studies indicate that epigenetic signatures, driving the shift between normal and diseased aging, can be acquired during the first stages of life, even in utero, and manifest phenotypically later on in life. Therefore, we decided to test whether SAM supplementation during the perinatal period (i.e., supplementing the mothers from mating to weaning) could exert a protective role towards AD-like symptom manifestation. We therefore compared the effect of post-weaning vs. perinatal SAM treatment in TgCRND8 mice by assessing PSEN1 methylation and expression and the development of amyloid plaques. We found that short-term perinatal supplementation was as effective as the longer post-weaning supplementation in repressing PSEN1 expression and amyloid deposition in adult mice. These results highlight the importance of epigenetic memory and methyl donor availability during early life to promote healthy aging and stress the functional role of non-CpG methylation.
Marco Fiore, Antonio Minni, Luca Cavalcanti, Giammarco Raponi, Gianluca Puggioni, Alessandro Mattia, Sara Gariglio, Andrea Colizza, Piero Giuseppe Meliante, Federica Zoccali,et al.
MDPI AG
Alcohol consumption is associated with oxidative stress and an increased risk of carcinoma of the upper aero-digestive tract (UADT). Recently, it has been found that some microorganisms in the human oral cavity may locally metabolize ethanol, forming acetaldehyde, a carcinogenic metabolite of alcohol. In a cohort of patients first visited for UADT cancers, we estimated their alcohol consumption by measuring Ethyl Glucuronide/EtG (a long-lasting metabolite of ethanol) in the hair and carbohydrate-deficient transferrin/CDT (short-term index of alcohol intake) in the serum. Moreover, we analyzed, by culture-based methods, the presence of Neisseria subflava, Streptococcus mitis, Candida albicans, and glabrata (microorganisms generating acetaldehyde) in the oral cavity. According to the EtG values, we correlated drinking alcohol with endogenous oxidative stress and the investigated microorganism’s presence. We found that 55% of heavy drinkers presented microorganisms generating acetaldehyde locally. Moreover, we found that the presence of oral acetaldehyde-producing bacteria correlates with increased oxidative stress compared to patients without such bacteria. As for the study of alcohol dehydrogenase gene polymorphisms (the enzyme that transforms alcohol to acetaldehyde), we found that only the “CGTCGTCCC” haplotype was more frequent in the general population than in carcinoma patients. This pilot study suggests the importance of estimating alcohol consumption (EtG), the presence of bacteria producing acetaldehyde, and oxidative stress as risk factors for the onset of oral carcinomas.
Fiorenza Pennacchia, Eqrem Rusi, Wael Abu Ruqa, Maria Antonella Zingaropoli, Patrizia Pasculli, Giuseppina Talarico, Giuseppe Bruno, Christian Barbato, Antonio Minni, Luigi Tarani,et al.
MDPI AG
Background: Since its outbreak, Coronavirus disease 2019 (COVID-19), a life-threatening respiratory illness, has rapidly become a public health emergency with a devastating social impact. Lately, the Omicron strain is considered the main variant of concern. Routine blood biomarkers are, indeed, essential for stratifying patients at risk of severe outcomes, and a huge amount of data is available in the literature, mainly for the previous variants. However, only a few studies are available on early routine biochemical blood biomarkers for Omicron-afflicted patients. Thus, the aim and novelty of this study were to identify routine blood biomarkers detected at the emergency room for the early prediction of severe morbidity and/or mortality. Methods: 449 COVID-19 patients from Sapienza University Hospital of Rome were divided into four groups: (1) the emergency group (patients with mild forms who were quickly discharged); (2) the hospital ward group (patients that after the admission in the emergency department were hospitalized in a COVID-19 ward); (3) the intensive care unit (ICU) group (patients that after the admission in the emergency department required intensive assistance); (4) the deceased group (patients that after the admission in the emergency department had a fatal outcome). Results: ANOVA and ROC data showed that high-sensitivity troponin-T (TnT), fibrinogen, glycemia, C-reactive protein, lactate dehydrogenase, albumin, D-dimer myoglobin, and ferritin for both men and women may predict lethal outcomes already at the level of the emergency department. Conclusions: Compared to previous Delta COVID-19 parallel emergency patterns of prediction, Omicron-induced changes in TnT may be considered other early predictors of severe outcomes.
Sergio Terracina, Antonio Pallaria, Marco Lucarelli, Antonio Angeloni, Annarita De Angelis, Flavio Maria Ceci, Brunella Caronti, Silvia Francati, Giovanna Blaconà, Marco Fiore,et al.
MDPI AG
Urinalysis is commonly used as a screening tool for kidney disease. In many cases, the dipstick urine assay includes the assessment of albumin/protein and creatinine; consequently, the value of their ratio is available on the urine section report. Identification of albuminuria/proteinuria at early stages is an important issue to prevent or at least delay the onset of chronic kidney disease (CKD), kidney failure, and the progression of cardiovascular damage linked to the kidney’s loss of function. Sensitive and specific diagnostic methods are required for the assessment of such an important biomarker: urine albumin, creatinine, and their ratio (ACR) measured with quantitative assays are considered the gold standard. Routine dipstick methods (more rapid and at a lower cost) are intended for wide population screening. The aim of our study was to verify the reliability of an automated urinalysis dipstick method by comparing the results with the quantitative test of creatinine and albumin performed on a clinical chemistry platform. The first-morning voids of 249 patients who arrived from different departments were analyzed in the Central Laboratory of the University Hospital Policlinico Umberto I in Rome. We found a good correlation between the two assays, even though we observed that the dipstick assessment tends to overestimate the ACR’s value, disclosing a higher number of false positives if compared to the reference method. As an important novelty in this study, we analyzed our data considering age (starting from pediatric to geriatric patients) and sex as variables for a sub-stratification of the participants. Our results show that positive values need to be confirmed with quantitative methods, especially in women and younger people, and that from samples that resulted as diluted at the dipstick assay, the ACR’s values can be obtained if they are reanalyzed with quantitative assays. Moreover, patients with microalbuminuria (ACR 30–300 mg/g) or severe albumin urinary excretion (ACR > 300 mg/g) should be reanalyzed using quantitative methods to obtain a more reliable calculation of the ACR.