Mara Massimi

Acrylamide, a contaminant formed during high-temperature cooking of common foods, is increasingly recognized as a silent and underestimated contributor to liver injury. In this editorial, we comment on the study by Nour El Deen et al , demonstrating that a chemically standardized ginger (Zingiber officinale ) extract (≥ 20% 6-gingerol) mitigates acrylamide-induced hepatotoxicity in rats through antioxidant, anti-inflammatory, and cytoprotective mechanisms. By combining biochemical, histopathological, and molecular evidence, the authors establish a coherent experimental basis for future translational research. Their results are consistent with a growing body of data supporting the hepatoprotective properties of ginger and emphasize the importance of using standardized nutraceutical preparations in preventive hepatology. From a precision-nutrition perspective, ginger phytocompounds appear to influence key oxidative, inflammatory, and metabolic pathways, possibly involving the gut-liver axis. Confirmatory studies in chronic exposure models and human cohorts, together with compositional and protein-level validation, will be essential to strengthen both the mechanistic and translational significance of these findings.

Liver diseases are among the most insidious and life-threatening conditions due to their progressive nature and late symptom onset. Cirrhosis and hepatocellular carcinoma account for most liver-related deaths, often following the progression from fibrosis. Fibrosis creates a hostile microenvironment, characterized by portal hypertension, vascular capillarization, intrahepatic vasoconstriction, and extracellular matrix deposition, which severely limits drug efficacy. Advances in pharmaceutical science have prompted efforts to develop liver-targeted drug delivery systems to prevent or reduce the progression of fibrosis, a central feature of many liver diseases. Fibrosis often reduces the in vivo efficacy of both approved and experimental drugs, underscoring the need for improved delivery strategies focused on stability, controlled release, and precise targeting. Nanoparticle (NP)-based systems show promise, either by delivering therapeutic agents, or in some cases, by contributing directly to the therapeutic effects. This review summarizes the main types of NPs explored for liver disease treatment, especially those aiming to reverse fibrosis or prevent its progression, a critical therapeutic target in chronic liver diseases. Additionally, it examines gene delivery and ultrasound-guided microbubble strategies, which can be combined with NPs to improve cell-specific targeting and boost therapeutic effects. Together, these approaches have the potential to address current therapeutic challenges and accelerate the development of liver-targeted treatments for clinical application.

Artemisia eriantha is a subendemic species of the Central Apennine, valued locally for its applications in ancient and traditional medicine for its antibacterial, antifungal, anthelmintic, digestive, and antispasmodic effects. Several of these properties are also found in other species within the same genus, including recent findings highlighting their anti-tumor actions. However, the presence of cytotoxic or anti-tumor activity has never been studied in A. eriantha. The aim of this study was thus to assess the potential anti-proliferative, pro-apoptotic, and antimetastatic effects of this plant using in vitro models of hepatocarcinoma cells (HepG2 and Huh7 cells). Treatment with A. eriantha extract (130 μg/mL) resulted in the reduced proliferation of HepG2 and Huh7 cells, driven by the dysregulation of proteins involved in the cell cycle (such as cyclin D1, cyclin E, and p27) and the activation of the p53-p21 pathway, leading to an increase in apoptotic activity. In addition, the treatment also lowered the healing capability after scratch wounds in Huh7 cells, which are characterized by a remarkable migratory capacity, suggesting that the A. eriantha extract may also be effective in controlling the migration and spread of metastatic cells. In conclusion, A. eriantha extract 130 μg/mL appears to interfere with key factors of HepG2 and Huh7 cell proliferation and invasion and emerges as a potential new adjuvant for the prevention and/or treatment of hepatocellular carcinoma. Additional research is necessary to establish if the effects observed are cell-specific and to elucidate the mechanisms of action and signaling pathways underlying its effectiveness.

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.

Phosphodiesterases (PDEs) are ubiquitous enzymes that hydrolyse cAMP and cGMP second messengers temporally, spatially, and integratedly according to their expression and compartmentalization inside the cell

Hepatocellular carcinoma is today the sixth leading cause of cancer-related death worldwide, despite the decreased incidence of chronic hepatitis infections. This is due to the increased diffusion of metabolic diseases such as the metabolic syndrome, diabetes, obesity, and nonalcoholic steatohepatitis (NASH). The current protein kinase inhibitor therapies in HCC are very aggressive and not curative. From this perspective, a shift in strategy toward metabolic therapies may represent a promising option. Here, we review current knowledge on metabolic dysregulation in HCC and therapeutic approaches targeting metabolic pathways. We also propose a multi-target metabolic approach as a possible new option in HCC pharmacology.

Phosphodiesterases (PDEs) are a superfamily of evolutionarily conserved cyclic nucleotide (cAMP/cGMP)-hydrolyzing enzymes, components of transduction pathways regulating crucial aspects of cell life. Within this family, the cGMP-dependent PDE5 is the major hydrolyzing enzyme in many mammalian tissues, where it regulates a number of cellular and tissular processes. Using Kluyveromyces lactis as a model organism, the murine PDE5A1, A2 and A3 isoforms were successfully expressed and studied, evidencing, for the first time, a distinct role of each isoform in the control, modulation and maintenance of the cellular redox metabolism. Moreover, we demonstrated that the short N-terminal peptide is responsible for the tetrameric assembly of MmPDE5A1 and for the mitochondrial localization of MmPDE5A2. We also analyzed MmPDE5A1, A2 and A3 using small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), structural mass spectrometry (MS) and polyacrylamide gel electrophoresis in their native conditions (native-PAGE) and in the presence of redox agents. These analyses pointed towards the role of a few specific cysteines in the isoforms’ oligomeric assembly and the loss of enzymatic activity when modified.

3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a family of evolutionarily conserved cAMP and/or cGMP hydrolyzing enzymes, components of transduction pathways regulating crucial aspects of cell life. Among them, cGMP-specific PDE5—being a regulator of vascular smooth muscle contraction—is the molecular target of several drugs used to treat erectile dysfunction and pulmonary hypertension. Production of full-length murine PDE5A isoforms in the milk-yeast Kluyveromyces lactis showed that the quaternary assembly of MmPDE5A1 is a mixture of dimers and tetramers, while MmPDE5A2 and MmPDE5A3 only assembled as dimers. We showed that the N-terminal peptide is responsible for the tetramer assembly of MmPDE5A1, while that of the MmPDE5A2 is responsible for its mitochondrial localization. Overexpression of the three isoforms alters at different levels the cAMP/cGMP equilibrium as well as the NAD(P)⁺/NAD(P)H balance and induces a metabolic switch from oxidative to fermentative. In particular, the mitochondrial localization of MmPDE5A2 unveiled the existence of a cAMP-cGMP signaling cascade in this organelle, for which we propose a metabolic model that could explain the role of PDE5 in some cardiomyopathies and some of the side effects of its inhibitors.

Isoform D of type 4 phosphodiesterase (PDE4D) has recently been associated with several human cancer types with the exception of human hepatocellular carcinoma (HCC). Here we explored the role of PDE4D in HCC. We found that PDE4D gene/protein were over-expressed in different samples of human HCCs compared to normal livers. Accordingly, HCC cells showed higher PDE4D activity than non-tumorigenic cells, accompanied by over-expression of the PDE4D isoform. Silencing of PDE4D gene and pharmacological inhibition of protein activity by the specific inhibitor Gebr-7b reduced cell proliferation and increased apoptosis in HCC cells, with a decreased fraction of cells in S phase and a differential modulation of key regulators of cell cycle and apoptosis. PDE4D silencing/inhibition also affected the gene expression of several cancer-related genes, such as the pro-oncogenic insulin growth factor (IGF2), which is down-regulated. Finally, gene expression data, available in the CancerLivER data base, confirm that PDE4D over-expression in human HCCs correlated with an increased expression of IGF2, suggesting a new possible molecular network that requires further investigations. In conclusion, intracellular depletion/inhibition of PDE4D prevents the growth of HCC cells, displaying anti-oncogenic effects. PDE4D may thus represent a new biomarker for diagnosis and a potential adjuvant target for HCC therapy.