Rossella Rotondo

Background: Methyltransferase-like 26 (METTL26) is a poorly characterized member of the METTL family that has been included in previous pan-cancer analyses, but its disease-specific clinical and molecular relevance in head and neck squamous cell carcinoma (HNSCC) and oral squamous cell carcinoma (OSCC) remains poorly defined. The aim of this study was to investigate METTL26 expression and its potential clinical and biological relevance in HNSCC, with particular attention to OSCC. Methods: The TCGA-HNSC dataset was used as a discovery dataset. METTL26 expression and pathological stage were evaluated using GEPIA3, whereas survival associations were analyzed in R. Tumor microenvironment associations were investigated using TIMER3. Genes co-expressed with METTL26 were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, while protein interaction networks were explored using STRING. These discovery analyses were performed using the heterogeneous TCGA-HNSC cohort, whereas two independent OSCC cohorts (GSE37991 and GSE30784) were primarily used to validate differential expression. Results: METTL26 expression was significantly increased in TCGA-HNSC compared to normal tissues and was associated with pathological stage. High METTL26 expression showed a non-significant trend toward poorer OS and PFI and was not independently associated with either outcome after multivariable adjustment. A positive association with cancer-associated fibroblast (CAF) abundance was detected using TIDE, whereas an inverse association with endothelial cell abundance was observed across multiple algorithms. Functional analysis showed enrichment of mitochondrial gene expression, mitochondrial translation, ribosomal functions, oxidative phosphorylation, and reactive oxygen species-related pathways. METTL26 was also positively correlated with several genes involved in therapy response such as PTOV1, MIF, BAD, and EIF3C. Importantly, METTL26 upregulation was independently confirmed in both OSCC cohorts, GSE37991 and GSE30784. Conclusions: METTL26 upregulation was independently confirmed in two OSCC cohorts, supporting its potential relevance as an expression biomarker. In contrast, the observed associations with pathological stage, mitochondrial and redox-related programs, stromal composition, and therapy-response-related genes should be considered exploratory and hypothesis-generating and require independent and functional validation.

Head and neck cancers (HNCs) represent a major global health burden and remain associated with substantial morbidity and limited therapeutic options, particularly in advanced or recurrent disease. Increasing interest has focused on naturally derived bioactive compounds with potential chemopreventive and therapeutic properties. Sulforaphane, a dietary xenobiotic isothiocyanate derived from glucoraphanin in cruciferous vegetables, has attracted attention due to its ability to modulate redox balance, epigenetic regulation, and multiple oncogenic signaling pathways. This manuscript reviews current evidence regarding the biological effects of sulforaphane in HNCs. Particular attention is given to the molecular mechanisms underlying its modulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a key regulator of cellular antioxidant and detoxification responses that can be activated by sulforaphane. Several studies indicate that sulforaphane can inhibit tumor growth through several mechanisms beyond Nrf2 activation, including induction of apoptosis, cell cycle arrest, epigenetic modulation, and suppression of oncogenic signaling pathways. In addition, sulforaphane has been shown to enhance the efficacy of conventional treatments, including chemotherapy, radiotherapy, and photodynamic therapy. Overall, the literature suggests that sulforaphane may represent a promising chemopreventive or therapeutic adjunct in HNC, although further clinical investigation is required to clarify its translational potential.

Background and aims: Parkinson’s disease (PD) is a neurodegenerative disorder for which no disease-modifying therapy currently exists, making it crucial to investigate alternative strategies that may slow its progression. The PRIME study will investigate the effects of combined dietary and physical activity interventions- performed in rehabilitative settings with health professional supervision and evaluation, versus single interventions on the gut microbiome in PD. The aim is to identify microbiome profiles – comparing traditional 16s rRNA gene sequencing with the third-generation method – as potential non-invasive, stage specific biomarkers of PD. In addition, the study will assess whether the combined intervention affects disease progression, symptoms, cognitive abilities, and quality of life. Methods: Eighty participants with PD will be randomized into four arms: a Mediterranean-diet intervention group; a structured physical-activity group; a combination group receiving both dietary and exercise interventions; a control group receiving standard care only. Conclusion: By integrating microbiome characterization with the evaluation of these interventions, the study aims to explore whether intervention-induced changes in the microbiota are associated with clinical improvement in PD, thus paving the way for the design of future non-pharmacological protocols to slow disease progression, mitigate symptom severity, and promote diagnosis. Clinical trial registration: https://clinicaltrials.gov/ , identifier NCT07097103.

Homocysteine, a sulfur-containing amino acid, is an intermediate product during the metabolism of methionine, a vital amino acid. An elevated concentration of homocysteine in the plasma, named hyperhomocysteinemia, has been significantly related to the onset of several diseases, including diabetes, multiple sclerosis, osteoporosis, cancer, and neurodegenerative disorders such as dementia, Alzheimer’s and Parkinson’s diseases. An interaction between metabolic pathways of homocysteine and gut microbiota has been reported, and specific microbial signatures have been found in individuals experiencing hyperhomocysteinemia. Furthermore, some evidence suggests that gut microbial modulation may exert an influence on homocysteine levels and related disease progression. Conventional approaches for managing hyperhomocysteinemia typically involve dietary interventions alongside the administration of supplements such as B vitamins and betaine. The present review aims to synthesize recent advancements in understanding interventions targeted at mitigating hyperhomocysteinemia, with a particular emphasis on the role of gut microbiota in these strategies. The emerging therapeutic potential of gut microbiota has been reported for several diseases. Indeed, a better understanding of the complex interaction between microbial species and homocysteine metabolism may help in finding novel therapeutic strategies to counteract hyperhomocysteinemia.