Sirtuins genes are widely distributed by evolution and have been found in eubacteria, archaea and eukaryotes. While prokaryotic and archeal species usually have one or two sirtuin homologs, in humans as well as in eukaryotes we found multiple versions and in mammals this family is comprised of seven different homologous proteins being all NAD-dependent de-acylases. 3D structures of human SIRT2, SIRT3, and SIRT5 revealed the overall conformation of the conserved core domain but they were unable to give a structural information about the presence of very flexible and dynamically disordered regions, the role of which is still structurally and functionally unclear. Recently, we modeled the 3D-structure of human SIRT1, the most studied member of this family, that unexpectedly emerged as a member of the intrinsically disordered proteins with its long disordered terminal arms. Despite clear similarities in catalytic cores between the human sirtuins little is known of the general structural characteristics of these proteins. The presence of disorder in human SIRT1 and the propensity of these proteins in promoting molecular interactions make it important to understand the underlying mechanisms of molecular recognition that reasonably should involve terminal segments. The mechanism of recognition, in turn, is a prerequisite for the understanding of any functional activity. Aim of this work is to understand what structural properties are shared among members of this family in humans as well as in other organisms.

Cancer research faces significant biological, technological, and systemic limitations that hinder the development of effective therapies and improved patient outcomes. Traditional preclinical models, such as 2D and 3D cell cultures, murine xenografts, and organoids, often fail to reflect the complexity of human tumor architecture, microenvironment, and immune interactions. This discrepancy results in promising laboratory findings not always translating effectively into clinical success. A core obstacle is tumor heterogeneity, characterized by diverse genetic, epigenetic, and phenotypic variations within tumors, which complicates treatment strategies and contributes to drug resistance. Hereditary malignancies and cancer stem cells contribute strongly to generating this complex panorama. Current early detection technologies lack sufficient sensitivity and specificity, impeding timely diagnosis. The tumor microenvironment, with its intricate interactions and resistance-promoting factors, further promotes treatment failure. Additionally, we only partially understand the biological processes driving metastasis, limiting therapeutic advances. Overcoming these barriers involves not only the use of new methodological approaches and advanced technologies, but also requires a cultural effort by researchers. Many cancer studies are still essentially observational. While acknowledging their significance, it is crucial to recognize the shift from deterministic to indeterministic paradigms in biomedicine over the past two to three decades, a transition facilitated by systems biology. It has opened the doors of deep metabolism where the functional processes that control and regulate cancer progression operate. Beyond biological barriers, systemic challenges include limited funding, regulatory complexities, and disparities in cancer care access across different populations. These socio-economic factors exacerbate research stagnation and hinder the translation of scientific innovations into clinical practice. Overcoming these obstacles requires multidisciplinary collaborations, advanced modeling techniques that better emulate human cancer, and innovative technologies for early detection and targeted therapy. Strategic policy initiatives must address systemic barriers, promoting health equity and sustainable research funding. While the complexity of cancer biology and systemic challenges are formidable, ongoing scientific progress and collaborative efforts inspire hope for breakthroughs that can transform cancer diagnosis, treatment, and survival outcomes worldwide.

The need to explore new alternative therapeutic strategies and chemoprevention methods for hepatocellular carcinoma is growing significantly. Selenium is a trace element that plays a critical role in physiological processes, and is used in cancer chemoprevention. The aim of this work was to test in vitro the effect of sodium selenite on the human hepatoma cell lines, HepG2 and Huh7, to assess its effect on the expression of GPX1, SELK and SELENBP1 and also to evaluate its action on inflammation determinants such as cytokines. Our results show that: (i) the increase observed for the GPX1 and SELK expression is correlated with an increase in the sodium selenite concentration, also evidencing an inverse association between the levels of these two proteins and SELENBP1; (ii) the selenium concentrations evaluated in protein extracts increase in proportional way with the selenite concentrations used in the treatment, suggesting that other selenoproteins can also be modulated and should be evaluated in further studies, and (iii) some cytokines, VEGF and three pro-inflammatory cytokines, i.e., IL-6, IL-8, and IL-17, decreased with an increasing selenite concentration. Finally, interactomic studies show that GPX1 and SELK, and the four pro-inflammatory cytokines are functionally correlated evidencing a putative anti-inflammatory role for the selenite.

Sirt-1 is defined as a nuclear protein involved in the molecular mechanisms of inflammation and neurodegeneration through the de-acetylation of many different substrates even if experimental data in mouse suggest both its cytoplasmatic presence and nucleo-cytoplasmic shuttling upon oxidative stress. Since the experimental structure of human Sirt-1 has not yet been reported, we have modeled its 3D structure, highlighted that it is composed by four different structural regions: N-terminal region, allosteric site, catalytic core and C-terminal region, and underlined that the two terminal regions have high intrinsic disorder propensity and numerous putative phosphorylation sites. Many different papers report experimental studies related to its functional activators because Sirt-1 is implicated in various diseases and cancers. The aim of this article is (i) to present interactomic studies based human Sirt-1 to understand its most important functional relationships in the light of the gene-protein interactions that control major metabolic pathways and (ii) to show by docking studies how this protein binds some activator molecules in order to evidence structural determinants, physico-chemical features and those residues involved in the formation of complexes.

Hepatitis C virus (HCV) infection can present as an acute manifestation, and can lead to severe complications such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). It represents a global health problem because there is no vaccine currently available. Cytokines play an important role in viral clearance, infection control, inflammation, regeneration and fibrosis, and also are implicated in the pathological processes occurring in the liver during viral infection. Immunological markers of chronic HCV hepatitis progression as compared to cirrhosis and HCC would be extremely useful, particularly for distinguishing between the molecules produced during HCV-induced chronic inflammation and those secreted during cirrhosis and HCC. In this work, we evaluated the serum levels of several cytokines, chemokines and growth factors in 30 patients affected by chronic HCV (HC), 30 patients affected by HCV-related cirrhosis (LC) and 20 healthy, control subjects. We used a multiplex biometric ELISA-based immunoassay in order to identify molecules that might be useful for monitoring the progression of HCV to liver cirrhosis and, possibly, to cancer. Our results show that some pro-inflammatory molecules are significantly up-regulated, and play a role as immunological markers in the intermediate steps towards liver cancer, and that hepatocyte growth factor (HGF) is a specific marker of liver cirrhosis. Finally, these data will be used to define a cytokinome profile, which might prove useful for studies involving the transition of chronic inflammation to neoplastic processes.

Many studies have evidenced that the phenolic components from flaxseed (FS) oil have potential health benefits. The effect of the phenolic extract from FS oil has been evaluated on two human breast cancer cell lines, MCF7 and MDA-MB231, and on the human non-cancerous breast cell line, MCF10A, by SRB assay, cellular death, cell cycle, cell signaling, lipid peroxidation and expression of some key genes. We have evidenced that the extract shows anti-proliferative activity on MCF7 cells by inducing cellular apoptosis, increase of the percentage of cells in G0/G1 phase and of lipid peroxidation, activation of the H2AX signaling pathway, and upregulation of a six gene signature. On the other hand, on the MDA-MB2131 cells we verified only an anti-proliferative activity, a weak lipid peroxidation, the activation of the PI3K signaling pathway and an up-regulation of four genes. Overall these data suggest that the extract has both cytotoxic and pro-oxidant effects only on MCF7 cells, and can act as a metabolic probe, inducing differences in the gene expression. For this purpose, we have performed an interactomic analysis, highlighting the existing associations. From this approach, we show that the phenotypic difference between the two cell lines can be explained through their differential response to the phenolic extract.