Giosuè Costa

Background: The in vivo accumulation of Advanced Glycation End products (AGEs) is associated with the development of several chronic aging-related and degenerative diseases, as they alter protein structures and activate oxidative and inflammatory processes through interactions with the receptor for AGEs (RAGE). Plant secondary metabolites play a key role in counteracting the glycation process through various mechanisms of action. Therefore, Aloysia citrodora leaf polyphenolic extract could represent a source of anti-glycative compounds. Methods: The methanolic extract was characterized by RP-HPLC-DAD-MSⁿ, and its anti-glycative properties were investigated using several in vitro assays mimicking the different steps of the glycation reaction. In parallel, molecular docking studies were carried out to evaluate potential interactions between the identified metabolites and RAGE. Furthermore, A. citrodora metabolites’ stability under simulated in vitro digestion was assessed, and the anti-glycative activity of the bioaccessible fraction was investigated. Results:A. citrodora extract, rich in iridoid glycosides, phenylethanoid glycosides, and flavones, strongly inhibited AGE formation (from 10% to 100%) in both the middle and end step of the reaction and had high methylglyoxal and glyoxal trapping capacity. However, the digestion process affected extract stability, particularly under intestinal conditions, yielding an overall bioaccessibility of about 40% and leading to a subsequent reduction in anti-glycative properties. Finally, molecular modeling analysis highlighted the ability of the studied metabolites to bind RAGE. Conclusions:A. citrodora represents a promising source of natural anti-glycative agents with potential applications as food ingredients. However, it is essential to improve the extract bioaccessibility and to preserve its anti-glycative properties by developing a suitable formulation.

Hazelnut cultivation is a strategic agricultural sector in Italy, with Calabria contributing through the native “Tonda Calabrese” cultivar, valued for its biodiversity. Despite its importance, data on the nutritional and compositional characteristics of this cultivar remain limited. In this study, hazelnuts from three different Calabrian producers were analyzed for morphological traits, proximate composition, and elemental content, using both conventional and non-destructive techniques such as CIELab color profiling and ATR-FTIR spectroscopy. The nuts showed high levels of essential micro-elements (Fe, Cu, Zn), aligning with previous findings on other cultivars, and showed no detectable pesticide residues, confirming their nutritional quality. Moreover, this study also aims to explore sustainable valorization strategies for hazelnut by-products, embracing circular economy principles in a “zero waste” approach, including oils and defatted flours. The extracted oils were evaluated for oxidative stability (peroxide value, p-anisidine, TOTOX index) and acidity, meeting Codex Alimentarius quality standards. The residual defatted flour was upcycled through eco-friendly methods, such as Ultrasound-Assisted Extraction (UAE) and Enzyme-Assisted Extraction (EAE), to isolate the polyphenol and protein fractions, respectively. Both extracts exhibited notable antioxidant activity (34.7–35.3 mmol Fe²⁺ eq/100 g and 64.3–82.2 mmol Fe²⁺ eq/100 g, respectively), suggesting their potential use as valuable ingredients for dietetic and nutraceutical applications.

Antimicrobial resistance poses a serious global health threat. Sortase A (SrtA), a membrane-bound cysteine transpeptidase responsible for anchoring key virulence factors to cell wall of Gram-positive bacteria, acts as critical driver of pathogenicity. Here, molecular dynamics simulations were employed to explore SrtA conformational flexibility and guide a structure-based virtual screening of approximately 300,000 natural compounds. Seven structurally diverse hits were selected based on their ability to bind the multiple conformations and their favorable docking scores. Drug-likeness and pharmacokinetic properties were predicted and compared with those of agents currently used against multidrug-resistant Staphylococcus aureus, revealing that the identified compounds obey both Lipinski’s and Muegge’s rules. In vitro assays confirmed the SrtA inhibitory activity of the two compounds in the low micromolar range. Noteworthy, both compounds significantly reduced S. aureus adhesion to fibrinogen, suggesting functional inhibition of endogenous bacterial SrtA. These findings support the potential of these natural scaffolds as antivirulence drug candidates.

Obesity remains a significant global health concern, with limited pharmacological options that balance efficacy and safety. In this study, we identified lithospermic acid (LTS0059529) from Salvia miltiorrhiza as a potential dual inhibitor of pancreatic lipase (PL) and human carbonic anhydrase VA (hCA VA), two key enzymes in lipid metabolism. Using molecular docking and dynamics simulations, we observed that lithospermic acid interacts with Zn²⁺ in hCA VA via its benzofuran carboxylate moiety and forms stable complexes with PL through hydrogen bonding with ASP 205 and π–stacking interactions with PHE 77 and PHE 215. Experimental validation confirmed its inhibitory activity, with K_i values of 33.1 ± 1.6 μM for PL and 0.69 ± 0.01 μM for hCA VA. While its inhibition of hCA VA is not isoform‐specific, lithospermic acid demonstrates significant potential as a dual inhibitor, targeting complementary pathways in obesity management. This study is the first to explore its dual action on PL and hCA VA, highlighting a promising strategy for future antiobesity therapies. Further research will focus on optimizing selectivity and potency to develop safer and more effective treatments.

Obesity is a global health crisis linked to chronic diseases like cardiovascular disease and type 2 diabetes. Its prevalence, even in low‐income countries, highlights the failure of traditional interventions. Safer pharmacological treatments are urgently needed, as many existing antiobesity drugs have been withdrawn due to severe side effects, leaving a critical therapeutic gap. A promising target in this context is human carbonic anhydrase V (hCA V), a mitochondrial enzyme that plays a key role in glucose homeostasis. Inhibiting hCA V has been shown to reduce lipogenesis and improve metabolic conditions. Natural plant extracts, such as silymarin from milk thistle, have demonstrated potential in managing obesity‐related metabolic syndromes by lowering triglycerides, reducing cholesterol levels, and improving liver function. Our computational studies have identified active compounds in silymarin that effectively inhibit hCA V, shedding light on a potential mechanism for its antiobesity effects. Building on these findings, our research further reveals that these compounds also inhibit carbonic anhydrase VII (hCA VII), enhancing their therapeutic potential. This dual inhibitory action addresses both metabolic dysregulation and oxidative stress. Notably, the antioxidant properties of hCA VII provide additional protection against obesity‐related complications by mitigating oxidative stress, a key contributor to the development of metabolic syndrome.

Ribonucleic acid (RNA)-binding proteins (RBPs) play a key role in regulating RNA stability, fate, function, gene expression, post-transcriptional modifications, and cellular activities. Among the various RBPs identified to date, the Hu proteins have been the most extensively studied. Specifically, HuR influences several cellular processes, including cell proliferation, differentiation, and stress response, and it is frequently overexpressed in various solid tumors. Several HuR ligands have been identified so far, highlighting the druggability of such a protein. To discover the novel HuR-RNA interfering agents, biophysical assays represent a promising approach. To overcome limitations for RNA manipulation, in this work, we explored the use of PNA (peptide nucleic acid) as an RNA analogue in interaction studies. Molecular modeling simulation revealed the ability of aegPNA to bind HuR and, therefore, the synthesis of the designed PNA was conducted. The saturation transfer difference (STD) nuclear magnetic resonance (NMR) technique was adopted to evaluate the ability of HuR ligands to interfere with the HuR-PNA complex, comparing the obtained results with RNAs. Our results evidenced that PNA may be considered a simple and valuable tool to analyze the interaction and interfering properties of HuR ligands by STD-NMR, thus improving the precision and reliability of the approach.

Recently, the comprehension of odor perception has advanced, unveiling the mysteries of the molecular receptors within the nasal passages and the intricate mechanisms governing signal transmission between these receptors, the olfactory bulb, and the brain. This review provides a comprehensive panorama of odors, encompassing various topics ranging from the structural and molecular underpinnings of odorous substances to the physiological intricacies of olfactory perception. It extends to elucidate the analytical methods used for their identification and explores the frontiers of computational methodologies.

Polyphenols, an important class of natural products, are widely distributed in plant-based foods. These compounds are endowed with several biological activities and exert protective effects in various physiopathological contexts, including cancer. We herein investigated novel potential mechanisms of action of polyphenols, focusing on the proteasome, which has emerged as an attractive therapeutic target in cancers such as multiple myeloma. We carried out a structure-based virtual screening study using the DrugBank database as a repository of FDA-approved polyphenolic molecules. Starting from 86 polyphenolic compounds, based on the theoretical binding affinity and the interactions established with key residues of the chymotrypsin binding site, we selected 2 promising candidates, namely Hesperidin and Diosmin. The further assessment of the biologic activity highlighted, for the first time, the capability of these two molecules to inhibit the β5-proteasome activity and to exert anti-tumor activity against proteasome inhibitor-sensitive or resistant multiple myeloma cell lines.