Vitamin B12 (VitB12) is a micronutrient and acts as a cofactor for fundamental biochemical reactions: the synthesis of succinyl-CoA from methylmalonyl-CoA and biotin, and the synthesis of methionine from folic acid and homocysteine. VitB12 deficiency can determine a wide range of diseases, including nervous system impairments. Although clinical evidence shows a direct role of VitB12 in neuronal homeostasis, the molecular mechanisms are yet to be characterized in depth. Earlier investigations focused on exploring the biochemical shifts resulting from a deficiency in the function of VitB12 as a coenzyme, while more recent studies propose a broader mechanism, encompassing changes at the molecular/cellular levels. Here, we explore existing study models employed to investigate the role of VitB12 in the nervous system, including the challenges inherent in replicating deficiency/supplementation in experimental settings. Moreover, we discuss the potential biochemical alterations and ensuing mechanisms that might be modified at the molecular/cellular level (such as epigenetic modifications or changes in lysosomal activity). We also address the role of VitB12 deficiency in initiating processes that contribute to nervous system deterioration, including ROS accumulation, inflammation, and demyelination. Consequently, a complex biological landscape emerges, requiring further investigative efforts to grasp the intricacies involved and identify potential therapeutic targets.

The deficiency of vitamins, a condition known as “hidden hunger”, causes comprehensive pathological states. Research over the years has identified a relationship between liver diseases and hypovitaminosis or defects in vitamin metabolism. The exact mechanisms remain elusive; however, the crucial involvement of specific vitamins in metabolic functions, alongside the reclassification of liver disease as metabolic dysfunction-associated steatotic liver disease (MASLD), has prompted researchers to investigate the potential cause-effect dynamics between vitamin deficiency and liver disease. Moreover, scientists are increasingly investigating how the deficiency of vitamins might disrupt specific organ crosstalk, potentially contributing to liver disease. Although the concept of a dysmetabolic circuit linking adipose tissue and the liver, leading to liver disease, has been discussed, the possible involvement of vitamin deficiency in this axis is a relatively recent area of study, with numerous critical aspects yet to be fully understood. In this review, we examine research from 2019 to July 2024 focusing on the possible link between liver-adipose tissue crosstalk and vitamin deficiency involved in the onset and progression of non-alcoholic fatty liver disease (NAFLD). Studies report that vitamin deficiency can affect the liver-adipose tissue axis, mainly affecting the regulation of systemic energy balance and inflammation.

Modification of DNA bases plays important roles in the epigenetic regulation of eukaryotic gene expression. Among the different types of DNA methylation, 5-methylcytosine (5mC) is common in higher eukaryotes. Although bisulfite sequencing is the established detection method for this modification, newer methods, such as Oxford nanopore sequencing, have been developed as quick and reliable alternatives. An earlier study using sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) indicated the presence of 5mC at very low concentration in Saccharomyces cerevisiae. More recently, a comprehensive study of the yeast genome found 40 5mC sites using the computational tool Nanopolish on nanopore sequencing output raw data. In the present study, we are trying to validate the prediction of the 5mC modifications in yeast with Nanopolish and two other nanopore software tools, Tombo and DeepSignal. Using publicly available genome sequencing data, we compared the open-access computational tools, including Tombo, Nanopolish and DeepSignal, for predicting 5mC. Our results suggest that these tools are indeed capable of predicting DNA 5mC modifications at a specific location from Oxford nanopore sequencing data. We also predicted that 5mC present in the S. cerevisiae genome might be located predominantly at the RDN locus of chromosome 12.

Recent studies have confirmed the direct role of vitamin B12 (VitB12) in the central nervous system (CNS) homeostasis; nevertheless, the detailed mechanisms are poorly understood. By analyzing RNA-Seq and microarray datasets obtained from databanks, this study aims to identify possible basic mechanisms, related to the brain, involved in altering the gene expression under VitB12 deficiency mimicking conditions. The database inquiry returned datasets generated from distinctly heterogeneous experimental sets and considering the quality and relevance requirements, two datasets from mouse and one from rat models were selected. The analyses of individual datasets highlighted a change in ribosomal gene expression in VitB12 deficiency mimicking conditions within each system. Specifically, a divergent regulation was observed depending on the animal model: mice showed a down regulation of the ribosomal gene expression, while rats an upregulation. Interestingly, E2f1 was significantly upregulated under VitB12 deficiency mimicking conditions in the animal models, with a greater upregulation in rats. The rat model also revealed putative E2F1 Transcription Factor Binding Sites (TFBSs) in the promoter of the differently regulated genes involved in ribosomal gene expression. This suggested the possibility that E2F1, being greater expressed in rats, could activate the ribosomal genes having E2F1 TFBSs, thus giving a plausible explication to the divergent regulation observed in animal models. Despite the great diversity of the experimental sets used to generate the datasets considered, a common alteration of the ribosomes exists, thereby indicating a possible basic and conserved response to VitB12 deficiency. Moreover, these findings could provide new insights on E2F1 and its association with CNS homeostasis and VitB12 deficiency. Graphical Abstract

Epidemiological data from assisted reproductive technologies (ART) link vitamin B12 (VitB12) deficiency to shorter gestation, low birth weight, and reduced live birth rates. VitB12 also plays a critical role in fertility for both sexes by supporting gamete quality. Despite some contradictions, emerging evidence suggests early‐life VitB12 deficiency may affect learning and cognitive development. Collectively, these findings suggest that VitB12 is a key determinant of both reproductive and developmental health. Mechanistically, VitB12 acts as a coenzyme in one‐carbon metabolism, and its deficiency leads to elevated homocysteine (Hcy) and methylmalonic acid (MMA) levels, promoting oxidative stress and thereby impairing fertility. Although this remains the most established mechanism, other yet unidentified pathways may also mediate the effects of VitB12 on reproductive function. While the effects of severe VitB12 deficiency are well established, mild deficiencies may develop silently in individuals following plant‐based diets or those with gastrointestinal disorders. Plant‐based sources of VitB12 remain controversial, as many provide only trace amounts or biologically inactive analogs such as pseudovitamin B12, which may interfere with absorption. Further research is needed to evaluate their bioavailability and clinical effectiveness. This review synthesizes clinical evidence, mechanistic insights, and dietary considerations to highlight how VitB12 status shapes reproductive health.

Vitamin B12 (VitB12) plays a crucial role in neural homeostasis, and a high dose is preferred as treatment to support recovery from neural impairments. However, a significant knowledge gap remains regarding its dose-dependent effects, particularly in its influence on cellular recovery following neural damage. To address this, we utilized retinoic acid-differentiated SH-SY5Y cells, as an in vitro neural model, where we induced neural damage using hydrogen peroxide (H ₂ O ₂ ), followed by recovery in either a physiological or high dose of VitB12. Our findings reveal that a physiological dose of VitB12 promotes more efficient recovery by enhancing cell survival and promoting neurite elongation after H ₂ O ₂ insult, compared to a high dose. Recovery with a physiological dose of VitB12 was associated with an early-stage (2 h) activation of antioxidant defenses, suggesting a quicker cellular response to oxidative stress than the high dose. At later stages (24 h), recovery with a physiological dose of VitB12 enhances mitochondrial metabolic activity and morphodynamics, alongside promoting lipid remodeling and increased formation of lipid droplets (LDs). These lipid-related processes may collectively contribute to mitigating oxidative damage and reinforcing cellular resilience during recovery. Overall, our study highlights that a physiological dose of VitB12 not only activates antioxidant defenses earlier than the high dose but also induces later-stage lipid remodeling, potentially supporting neural recovery and homeostasis. Graphical Abstract