Under physio-pathological conditions, cells release membrane-surrounded structures named Extracellular Vesicles (EVs), which convey their molecular cargo to neighboring or distant cells influencing their metabolism. Besides their involvement in the intercellular communication, EVs might represent a tool used by cells to eliminate unnecessary/toxic material. Here, we revised the literature exploring the link between EVs and redox biology. The first proof of this link derives from evidence demonstrating that EVs from healthy cells protect target cells from oxidative insults through the transfer of antioxidants. Oxidative stress conditions influence the release and the molecular cargo of EVs that, in turn, modulate the redox status of target cells. Oxidative stress-related EVs exert both beneficial or harmful effects, as they can carry antioxidants or ROS-generating enzymes and oxidized molecules. As mediators of cell-to-cell communication, EVs are also implicated in the pathophysiology of oxidative stress-related diseases. The review found evidence that numerous studies speculated on the role of EVs in redox signaling and oxidative stress-related pathologies, but few of them unraveled molecular mechanisms behind this complex link. Thus, the purpose of this review is to report and discuss this evidence, highlighting that the analysis of the molecular content of oxidative stress-released EVs (reminiscent of the redox status of originating cells), is a starting point for the use of EVs as diagnostic and therapeutic tools in oxidative stress-related diseases.

Lysosomes are acidic cell compartments containing a large set of hydrolytic enzymes. These lysosomal hydrolases degrade proteins, lipids, polysaccharides, and nucleic acids into their constituents. Materials to be degraded can reach lysosomes either from inside the cell, by autophagy, or from outside the cell, by different forms of endocytosis. In addition to their degradative functions, lysosomes are also able to extracellularly release their contents by lysosomal exocytosis. These organelles move from the perinuclear region along microtubules towards the proximity of the plasma membrane, then the lysosomal and plasma membrane fuse together via a Ca²⁺-dependent process. The fusion of the lysosomal membrane with plasma membrane plays an important role in plasma membrane repair, while the secretion of lysosomal content is relevant for the remodelling of extracellular matrix and release of functional substrates. Lysosomal storage disorders (LSDs) and age-related neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases, share as a pathological feature the accumulation of undigested material within organelles of the endolysosomal system. Recent studies suggest that lysosomal exocytosis stimulation may have beneficial effects on the accumulation of these unprocessed aggregates, leading to their extracellular elimination. However, many details of the molecular machinery required for lysosomal exocytosis are only beginning to be unravelled. Here, we are going to review the current literature on molecular mechanisms and biological functions underlying lysosomal exocytosis, to shed light on the potential of lysosomal exocytosis stimulation as a therapeutic approach.

Amiodarone is a cationic amphiphilic drug used as an antiarrhythmic agent. It induces phospholipidosis, i.e., the accumulation of phospholipids within organelles of the endosomal–lysosomal system. Extracellular vesicles (EVs) are membrane-enclosed structures released by any type of cell and retrieved in every fluid of the body. EVs have been initially identified as a system to dispose cell waste, but they are also considered to be an additional manner to transmit intercellular signals. To understand the role of EVs in drug-induced phospholipidosis, we investigated EVs release in amiodarone-treated HEK-293 cells engineered to produce fluorescently labelled EVs. We observed that amiodarone induces the release of a higher number of EVs, mostly of a large/medium size. EVs released upon amiodarone treatment do not display significant morphological changes or altered size distribution, but they show a dose-dependent increase in autophagy associated markers, indicating a higher release of EVs with an autophagosome-like phenotype. Large/medium EVs also show a higher content of phospholipids. Drugs inducing lysosomal impairment such as chloroquine and bafilomycin A1 similarly prompt a higher release of EVs enriched in autophagy markers. This result suggests a mechanism associated with amiodarone-induced lysosomal impairment more than a connection with the accumulation of specific undigested substrates. Moreover, the implementation of the lysosomal function by overexpressing TFEB, a master gene regulator of lysosomal biogenesis, prevents the amiodarone-induced release of EVs, suggesting that this could be a feasible target to attenuate drug-induced abnormalities.

Summary: LC/MS-based analysis techniques combined with specialized lipid tool allow for the qualitative and quantitative determination of thousands of lipid molecules. Some recent bioinformatics tools have been developed to study changes in the lipid profile in case–control experiments and correlate these changes to different enzyme activity or gene expression. However, the existing tools have the limitation to treat only the assembled lipid molecules. In reality, each individual molecule can be considered as an assembly of smaller parts, often called building blocks. These are the result of a myriad of biochemical synthesis and transformation processes that, from a systems biology perspective, should not be ignored. Here, we present LipidOne, a new lipidomic tool which highlights all qualitative and quantitative changes in lipid building blocks both among all detected lipid classes and among experimental groups. Thanks to LipidOne, even differences in lipid building blocks can now be linked to the activity of specific classes of enzymes, transcripts and genes. Availability and implementation: LipidOne software is freely available at www.dcbb.unipg.it/LipidOne and https://github.com/matteogiulietti/LipidOne. Contact: roberto.pellegrino@unipg.it Supplementary information: Supplementary data are available at Bioinformatics online.

Bidens pilosa L. (fam. Asteraceae) is an annual herb used globally in phytotherapy and each plant material or the whole plant have been declared to be effective. Therefore, the aim of the present study was to conduct metabolomic profiling of different plant materials, including the quali-quantitative composition of phenolic compounds. The intrinsic scavenging/reducing properties and antimicrobial effects of the extracts were assayed against numerous bacterial, Candida and dermatophytes species, whereas docking runs were conducted for tentatively unravelling the mechanism of action underlying antimicrobial effects. Oligosaccharide, disaccharide and fatty acids were present at higher concentrations in root rather than in the other plant parts. Monoglycerides were more abundant in stem than in the other plant parts, whereas peptide and diterpenoid were prominent in leaf and root, respectively. By contrast, amino acids showed very different distribution patterns in the four plant parts. Regarding the phenolic composition, appreciable levels of caftaric acid were found in most of the analyzed methanol extracts, that were also particularly efficacious as antiradical and anti-mycotic agents against C. albicans and dermatophytes. The docking experiments also showed a micromolar affinity of caftaric acid towards the lanosterol 14α-demethylase, deeply involved in fungal metabolism. In conclusion, the present study corroborates the B. pilosa as a phytotherapy remedy against infectious disease.

The growing interest in plant-origin active molecules with medicinal properties has led to a revaluation of plants in the pharmaceutical field. Plant-derived extracellular vesicles (PDEVs) have emerged as promising candidates for next-generation drug delivery systems due to their ability to concentrate and deliver a plethora of bioactive molecules. These bilayer membranous vesicles, whose diameter ranges from 30 to 1000 nm, are released by different cell types and play a crucial role in cross-kingdom communication between plants and humans. Notably, PDEVs have demonstrated efficacy in treating various diseases, including cancer, alcoholic liver disease, and inflammatory bowel disease. However, further research on plant vesicles is necessary to fully understand their traits and purposes. This study investigates the phototoxic effects of extracellular vesicles (EVs) from Aloe arborescens, Aloe barbadensis, and Aloe chinensis on the human melanoma cell line SK-MEL-5, focusing on their anthraquinone content, recognized as natural photosensitizers. The phototoxic impact of Aloe EVs is associated with ROS production, leading to significant oxidative stress in melanoma cells, as validated by a metabolome analysis. These findings suggest that EVs from Aloe arborescens, Aloe barbadensis, and Aloe chinensis hold promise as potential photosensitizers, thus highlighting their potential for future application in photodynamic cancer therapy and providing valuable insights into the possible utilization of PDEVs for therapeutic purposes.