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.
CFTR Modulator Response in Nasal Organoids Derived from People with Cystic Fibrosis Stefania Lo Cicero, Germana Castelli, Aurora Ceci, Anna Maria Cerio, Giovanna Blaconà, et al. Cells, 2025 Despite the progressive extension of CFTR variant eligibility to the triple combination of elexacaftor/tezacaftor/ivacaftor (ETI), most rare CFTR pathogenic variants remain ineligible for CFTR modulators. It is crucial to determine whether unexplored variants are rescuable by clinical modulators and to identify innovative therapeutic strategies for rescuing non-responder variants. The approach known as “theratyping” (in vitro testing of genotypes) has been accepted by the Food and Drug Administration (FDA) for the extension of clinical modulators’ approval for in vitro responding genotypes. We used one of the most advanced models for theratyping: organoids derived from nasal epithelia of people with cystic fibrosis (pwCF). We optimized the forskolin-induced swelling (FIS) of organoids to assess CFTR basal or modulator-restored function. Nasal organoids mimicked the original epithelial tissue, CFTR residual activity, and modulator response. We set up the FIS assay using nasal organoids with reference genotypes and theratyped 38 rare (non-F508del) CFTR genotypes, either eligible or non-eligible for FDA approval, for treatment with ETI or ivacaftor. We found strong correspondence between the in vitro response of CFTR variants to modulators and their FDA approval status. Additionally, some previously uncharacterized CFTR variants have proven responsive to clinical modulators, with significant therapeutic implications. These results suggest that the nasal organoid FIS assay, pending confirmation of the prediction in the corresponding pwCF, might be considered as a powerful in vitro tool to predict modulator efficacy in each pwCF, guiding out-of-label prescription in CF, and to identify uncharacterized variants responsive to modulators. This approach may allow comparison of the efficacy of different therapeutics or the identification of innovative strategies for non-responding genotypes, improving personalized therapy and quality of life for pwCF.
Oxidative stress – Alzheimer’s disease – DNA methylation: the role of arsenic Daniele Antinori, Marco Lucarelli, Andrea Fuso Essays in Biochemistry, 2025 Alzheimer’s disease (AD) is a neurodegenerative disease, representing the seventh cause of death worldwide and the first cause of dementia. Several pathogenic mechanisms have been connected to this pathology, including protein aggregation, oxidative stress, metabolic dysfunction, mitochondrial dysfunction, neuroinflammation, synaptic dysfunction, and cell death. The etiology of AD is multifactorial, suggesting that, in addition to a genetic component, the environment may strongly influence its onset and progression. Exposure to heavy metals, such as lead, cadmium, mercury, and arsenic (As), is known to be associated with AD, with As showing one of the strongest correlations, in relation to the epigenetic changes. The World Health Organization (WHO) set a very low limit for its concentration to 10 μg/l in drinking water. The possibility that As may induce epigenetic effects is a recent hypothesis. Evidence, so far, suggests that As may induce DNA hypomethylation in the brain, by mechanisms not yet completely disclosed. This minireview aims to provide evidence to support the role of As exposure in AD, maintaining a focus on oxidative stress and ferroptosis, with a perspective on DNA methylation.
One-carbon metabolism modulates miR-29a–DNA methylation crosstalk in Alzheimer's disease Tiziana Raia, Rosaria A. Cavallaro, Luiza Diniz Ferreira Borges, Stefano Cinti, Mariano Bizzarri, et al. Alzheimer S and Dementia, 2025 INTRODUCTIONAlzheimer's disease (AD)’s multifactorial nature stresses the role of epigenetics in affecting different pathological pathways. We demonstrated that one‐carbon metabolism epigenetically impacts AD‐like phenotype. Here, we investigated the crosstalk between methylation and microRNAs in AD.METHODSWe altered one‐carbon metabolism to induce hypo‐ and hyper‐methylation, in SK‐N‐BE neuroblastoma cells and TgCRND8 mice. miRNAs were profiled through a polymerase chain reaction array, then we focused on miR‐29a expression and methylation of its genomic locus. Finally, we assessed miR‐29a expression and methylation in the brain of AD subjects.RESULTSMiR‐29a was repressed in hypomethylating and expressed in hypermethylating conditions. The expression of miR‐29a and of its target, BACE1, was inversely correlated.DISCUSSIONWe demonstrated for the first time that miR‐29a is modulated by one‐carbon metabolism through DNA methylation, disclosing the molecular mechanisms regulating BACE1 expression in AD. These data confirm miR‐29a’s protective role in AD and support miR‐29a as a potential biomarker for AD.
miRNAs from Zebrafish Embryo Extracts Inhibit Breast Cancer Invasiveness and Migration by Modulating miR-218-5p/PI3K Pathway Noemi Monti, Daniele Antinori, Sara Proietti, Aurora Piombarolo, Alessandro Querqui, et al. International Journal of Molecular Sciences, 2025 Herein, we demonstrate that soluble factors extracted from the distinct phases of the development of zebrafish embryos (ZFEs) exhibit a specific miRNA profile. We removed proteins and concentrated miRNAs in different phase-related samples, which we investigated further. We observed that ZFEs modulate miRNA expression in both normal and cancerous breast cells, significantly inhibiting the invasiveness and motility of triple-negative breast cancer cells. Namely, ZFEs reactivate the synthesis of miR-218-5p in cancerous cells, leading to the downregulation of PI3K, which consequently alters the distribution of phosphoinositides (such as PIP2/PIP3). Moreover, the silencing of miR-218-5p abolished the ZFE effects. Restoring a proper PIP2/PIP3 ratio is crucial for promoting the regression of the malignant phenotype. Phenotypic reversion follows the extensive cytoskeleton rearrangement and the re-emergence of E-cadherin/β-catenin complexes. In addition, ZFEs antagonize the Epithelial Mesenchymal Transition (EMT) by modulating several pathways, including the TCTP-p53 axis. Overall, these results show that embryo extracts enriched with fish miRNAs reactivate endogenous miR-218-5p in cancerous cells, which in turn downregulates critical pathways involved in tumor progression and metastasis.
Alcohol Consumption and Autoimmune Diseases Sergio Terracina, Brunella Caronti, Marco Lucarelli, Silvia Francati, Maria Grazia Piccioni, et al. International Journal of Molecular Sciences, 2025 Alcohol is the second-most misused substance after tobacco. It has been identified as a causal factor in more than 200 diseases and 5.3% of all deaths and is associated with significant behavioral, social, and economic difficulties. As alcohol consumption may modulate the immune system’s regulatory mechanisms to avoid attacking the body’s tissues, it has been proven to play a dichotomic role in autoimmune diseases (ADs) based on the quantity of consumption. In this review, we report updated evidence on the role of alcohol in ADs, with a focus on alcohol addiction and the human biological immune system and the relationship between them, with alcohol as a risk or protective factor. Then, in this narrative review, we report the main evidence on the most studied ADs where alcohol represents a key modulator, including autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, diabetes, allergic rhinitis, and primary biliary cholangitis. Alcohol at low–moderate dosages seems mostly to have a protective role in these diseases, while at higher dosages, the collateral risks surpass possible benefits. The specific mechanisms by which low-to-moderate alcohol intake relieves AD symptoms are not yet fully understood; however, emerging studies suggest that alcohol may have a systemic immunomodulatory effect, potentially altering the balance of anti-inflammatory innate and adaptive immune cells, as well as cytokines (via the NF-κB or NLRP3 pathways). It might influence the composition of the gut microbiome (increasing amounts of beneficial gut microbes) and the production of their fatty acid metabolites, such as short-chain fatty acids (SCFAs) and polyunsaturated fatty acids (PUFAs), as well as elevated concentrations of acetate, high-density lipoprotein (HDL), and nitric oxide (NO). Unfortunately, a definite acceptable daily intake (ADI) of ethanol is complicated to establish because of the many mechanisms associated with alcohol consumption such that despite the interesting content of these findings, there is a limit to their applicability and risks should be weighed in cases of alcoholic drinking recommendations. The aim of future studies should be to modulate those beneficial pathways involved in the alcohol-protective role of ADs with various strategies to avoid the risks associated with alcohol intake.
Alcohol Consumption and Breast and Ovarian Cancer Development: Molecular Pathways and Mechanisms F. Fanfarillo, Brunella Caronti, Marco Lucarelli, Silvia Francati, Luigi Tarani, et al. Current Issues in Molecular Biology, 2024 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.
Italian Guidelines for the diagnosis and treatment of Fetal Alcohol Spectrum Disorders: clinical hallmarks Michela Menghi, Ginevra Micangeli, Roberto Paparella, M. Ceccanti, Giovanna Coriale, et al. Rivista Di Psichiatria, 2024 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.
Italian Guidelines for the diagnosis and treatment of Fetal Alcohol Spectrum Disorders: detecting alcohol drinking during pregnancy Giampiero Ferraguti, Francesca Fanfarillo, Simona Nicotera, Sergio Terracina, Clementina Moschella, et al. Rivista Di Psichiatria, 2024 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.
