Biochemistry, Genetics and Molecular Biology, Cell Biology, Endocrinology, Cancer Research
15
Scopus Publications
Scopus Publications
PCB 153 Modulates Genes Involved in Proteasome and Neurodegeneration-Related Pathways in Differentiated SH-SY5Y Cells: A Transcriptomic Study Aurelio Minuti, Serena Silvestro, Claudia Muscarà, Michele Scuruchi, Simone D’Angiolini Cells, 2026 Polychlorinated biphenyls (PCBs) are persistent environmental contaminants associated with neurotoxicity and increased risk of neurodegenerative diseases. PCB 153, a highly abundant non-coplanar congener, bioaccumulates in human tissues and impairs homeostasis. This study investigated the transcriptomic effects of PCB 153 (2,2′,4,4′,5,5′-Hexachlorobiphenyl) in retinoic acid (RA)-differentiated SH-SY5Y neuronal cells to identify early, sub-cytotoxic molecular alterations. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after 24 h exposure to increasing PCB 153 concentrations. RNA-Seq was performed on cells treated with 5 μM PCB 153, the highest non-cytotoxic dose. Sequencing reads were quality-filtered, aligned to the human genome, and analyzed with DESeq2. Functional enrichment was conducted using Gene Ontologies and KEGG pathways. Western blot analyses were performed to assess protein level changes in selected targets. RNA-Seq identified 1882 significantly altered genes (q-value < 0.05). Gene Ontology analysis revealed strong enrichment of proteasome-related terms, with most proteasomal subunits displaying coordinated upregulation. KEGG analysis further showed significant enrichment of Alzheimer’s (AD), Parkinson’s (PD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative disease pathways. These findings indicate that PCB 153 triggers a pronounced proteostatic response in neuron-like cells, suggesting early disruption of protein homeostasis that may contribute to mechanisms associated with neurodegeneration.
Polychlorinated Biphenyls, Oxidative Stress, and Brain Health: Mechanistic Links to Neurodegenerative and Neurodevelopmental Diseases Aurelio Minuti, Alessia Floramo, Veronica Argento, Ivan Anchesi, Claudia Muscarà, Marco Calabrò, Serena Silvestro Antioxidants, 2026 Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain widely detectable in the environment and human tissues decades after their ban, raising concerns for brain health. Both dioxin-like (DL) and non-dioxin-like (NDL) congeners interfere with neuronal function through partially distinct pathways, including aryl hydrocarbon receptor activation, disruption of calcium and dopaminergic signaling, oxidative stress, and epigenetic remodeling. Experimental and epidemiological studies indicate that developmental PCB exposure is associated with impaired cognition, attention, motor function, and increased risk of neurodevelopmental disorders. Furthermore, chronic exposure in adulthood has been linked to neurodegenerative diseases. At the cellular level, NDL-PCBs sensitize ryanodine receptors, alter dendritic and axonal growth, promote mitochondrial dysfunction, generate reactive oxygen and nitrogen species, and compromise blood–brain barrier integrity, thereby fostering neuroinflammation, synaptic dysfunction, and neuronal loss. This review synthesizes current evidence on the molecular and cellular mechanismtable s underlying PCB-induced neurotoxicity across the lifespan, highlighting oxidative stress as a central factor, integrating calcium dysregulation, neurotransmitter imbalance, and apoptotic and epigenetic pathways. Finally, potential neuroprotective roles of antioxidant strategies are discussed, emphasizing their relevance for mitigating PCB-related neurodevelopmental and neurodegenerative risk.
Genetic and epigenetic modulation of AHR pathway in GH-secreting pituitary tumors and effects on acromegaly clinical phenotype Aurelio MINUTI, Giuseppe GIUFFRIDA, Marta RAGONESE, Ylenia ALESSI, Francesco FERRAÙ, Salvatore CANNAVÒ Minerva Endocrinology, 2025 INTRODUCTION: Several data demonstrated that chemical pollutants can be endocrine disruptors and they have an important role in tumorigenic processes. It has been shown that pollution exposure can affect pituitary cells' function and biology, indeed an increased prevalence of acromegaly has been reported in highly polluted areas. EVIDENCE ACQUISITION: One transcription factor that has a role in both carcinogenesis and in xenobiotics' detoxification is the aryl hydrocarbon receptor (AHR). Its deregulation could have a pivotal role in pituitary tumors, especially in GH-secreting pituitary tumors. Environmental chemicals affect the expression and function of ncRNAs (miRNA, lncRNA and circRNA) through different mechanisms. EVIDENCE SYNTHESIS: However, to date, few data on the role of the environmental pollutants in the clinical expression and pathogenesis of GH-secreting pituitary tumors are available. CONCLUSIONS: This article presents a summary of the AHR signaling pathways that are triggered by various ligands and emphasizes the significant distinctions between the potential biological and toxicological effects of AHR gene activation. We also deepen the functions of ncRNAs and acromegaly and provide current data on their regulation by the AHR. Overall, more studies are still needed to fully understand the dynamic interplay between the AHR signaling pathway and ncRNAs in GH-secreting pituitary adenomas.
Psychedelics in Multiple Sclerosis: Mechanisms, Challenges, and Prospects for Neuroimmune Modulation and Repair Ivan Anchesi, Maria Francesca Astorino, Ivana Raffaele, Deborah Stefania Donato, Serena Silvestro, Aurelio Minuti, Marco Calabrò, Michele Scuruchi, Giovanni Luca Cipriano Cells, 2025 Multiple Sclerosis (MS) therapies effectively modulate peripheral immune responses but largely fail to promote neural repair within the central nervous system. This review evaluates whether psychedelic compounds (PSYs), via 5-HT2A activation, can fill a critical therapeutic gap: the need for agents that simultaneously suppress neuroinflammation and promote regeneration. We dissect the evidence suggesting PSYs can reprogram the neuroimmune milieu by downregulating key pro-inflammatory cytokines (e.g., TNF-α, IL-6) in glial cells while concurrently upregulating crucial neurotrophic factors (e.g., BDNF) that promote synaptic plasticity and oligodendrocyte support. However, we argue that the current evidence, largely derived from non-specific inflammation models, is insufficient to predict clinical efficacy in an autoimmune disease like MS. We critically analyze the significant translational barriers—from cardiovascular and psychiatric risks to profound legal and ethical challenges—that temper the immediate clinical promise. Finally, we propose a forward-looking perspective, suggesting that the true value of PSYs may lie not in their direct clinical use, but in uncovering novel therapeutic pathways. The emergence of non-hallucinogenic, functionally selective 5-HT2A agonists, inspired by psychedelic pharmacology, represents a more viable strategy to harness these mechanisms for MS therapy, demanding rigorous preclinical validation in disease-relevant models.
Computational Splicing Analysis of Transcriptomic Data Reveals Sulforaphane Modulation of Alternative mRNA Splicing of DNA Repair Genes in Differentiated SH-SY5Y Neurons Maria Lui, Luigi Chiricosta, Renato Iori, Emanuela Mazzon, Aurelio Minuti, Osvaldo Artimagnella International Journal of Molecular Sciences, 2025 Sulforaphane (SFN) is a bioactive compound belonging to the isothiocyanate family, known for its neuroprotective properties. While transcriptomic studies have highlighted SFN’s role in regulating gene expression, its impact on alternative splicing (AS), a key regulatory mechanism in neuronal metabolism, remains underexplored. In this study, we investigated whether SFN pre-treatment influences mRNA splicing patterns in an in vitro neuronal model using retinoic acid (RA)-differentiated SH-SY5Y cells. Using a dedicated RNA-seq-based splicing analysis pipeline, we identified 194 differential alternative splicing events (DASEs) associated with SFN treatment. Gene Ontology enrichment revealed significant over-representation of DNA repair processes. To better understand the functional implications, we integrated in silico predictions of premature stop codons, DASE/miRNA hybridizations, and DASE/RNA-binding protein (RBP) motif occurrences. Our findings suggest that SFN may modulate splicing of key DNA repair genes, contributing to protecting neurons against DNA damage. These preliminary results underscore a novel layer of SFN’s molecular effects and propose it as a valuable adjuvant in physiological conditions to enhance cellular health. Further studies are warranted to dissect the mechanistic underpinnings of SFN-mediated AS and its relevance in DNA-damage-related disorders.
Cannabinol’s Modulation of Genes Involved in Oxidative Stress Response and Neuronal Plasticity: A Transcriptomic Analysis Serena Silvestro, Marco Calabrò, Alessandra Trainito, Stefano Salamone, Federica Pollastro, Emanuela Mazzon, Aurelio Minuti Antioxidants, 2025 Cannabis sativa is a remarkable source of bioactive compounds, with over 150 distinct phytocannabinoids identified to date. Among these, cannabinoids are gaining attention as potential therapeutic agents for neurodegenerative diseases. Previous research showed that cannabinol (CBN), a minor cannabinoid derived from Δ9-tetrahydrocannabinol, exhibits antioxidant, anti-inflammatory, analgesic, and anti-bacterial effects. The objective of this study was to assess the protective potential of 24 h CBN pre-treatment, applied at different concentrations (5 µM, 10 µM, 20 µM, 50 µM, and 100 µM), in differentiated neuroblastoma × spinal cord (NSC-34) cells. Transcriptomic analysis was performed using next-generation sequencing techniques. Our results reveal that CBN had no negative impact on cell viability at the tested concentrations. Instead, it showed a significant effect on stress response and neuroplasticity-related processes. Specifically, based on the Reactome database, the biological pathways mainly perturbed by CBN pre-treatment were investigated. This analysis highlighted a significant enrichment in the Reactome pathway’s cellular response to stress, cellular response to stimuli, and axon guidance. Overall, our results suggest that CBN holds promise as an adjuvant agent for neurodegenerative diseases by modulating genes involved in neuronal cell survival and axon guidance.
Role and Functions of Irisin: A Perspective on Recent Developments and Neurodegenerative Diseases Aurelio Minuti, Ivana Raffaele, Michele Scuruchi, Maria Lui, Claudia Muscarà, Marco Calabrò Antioxidants, 2025 Irisin is a peptide derived from fibronectin type III domain-containing protein 5 (FNDC5) and is primarily produced by muscle fibers under the regulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) during exercise. Irisin has been the subject of extensive research due to its potential as a metabolic regulator and its antioxidant properties. Notably, it has been associated with protective actions within the brain. Despite growing interest, many questions remain regarding the molecular mechanisms underlying its effects. This review summarizes recent findings on irisin, highlighting its pleiotropic functions and the biological processes and molecular cascades involved in its action, with a particular focus on the central nervous system. Irisin plays a crucial role in neuron survival, differentiation, growth, and development, while also promoting mitochondrial homeostasis, regulating apoptosis, and facilitating autophagy—processes essential for normal neuronal function. Emerging evidence suggests that irisin may improve conditions associated with non-communicable neurological diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis. Given its diverse benefits, irisin holds promise as a novel therapeutic agent for preventing and treating neurological diseases.
Bioactivated Glucoraphanin Improves Cell Survival, Upregulating Phospho-AKT, and Modulates Genes Involved in DNA Repair in an In Vitro Alzheimer’s Disease Model: A Network-Transcriptomic Analysis Aurelio Minuti, Emanuela Mazzon, Renato Iori, Luigi Chiricosta, Osvaldo Artimagnella Nutrients, 2024 Background/Objectives: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, for which a definitive cure is still missing. Recently, natural compounds have been investigated for their possible neuroprotective role, including the bioactivated product of glucoraphanin (GRA), the sulforaphane (SFN), which is highly rich in cruciferous vegetables. It is known that SFN alleviates neuronal dysfunction, apoptosis, and oxidative stress in the brain. In the light of this evidence, the aim of this study was to investigate the molecular effects of SFN pre-treatment in differentiated SH-SY5Y neurons exposed to β-amyloid (Aβ). Methods: To this end, we first evaluated first cell viability via the Thiazolyl Blue Tetrazolium Bromide (MTT) assay, and then we analyzed the transcriptomic profiles by next-generation sequencing (NGS). Finally, we used a network analysis in order to understand which biological processes are affected, validating them by Western blot assay. Results: SFN pre-treatment counteracted Aβ-induced loss of cell viability. The network-transcriptomic analysis revealed that SFN upregulates genes associated with DNA repair, such as ABRAXAS1, BRCA1, BRCA2, CDKN1A, FANCA, FANCD2, FANCE, NBN, and XPC. Finally, SFN also increased the phosphorylation of AKT, which is associated with DNA repair and cell survival. Conclusions: These data suggest that SFN is a natural compound that could be suitable in the prevention of AD, thanks to its neuroprotective role in increasing cell survival, potentially restoring DNA damage induced by Aβ exposure.
