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Simple Summary: In this manuscript, we review the progress in knowledge made over the last decade, which, thanks to the commitment of many academics and researchers, has clarified many aspects relating to ferroptosis and its connections with cancer. Ferroptosis is currently regarded as a distinct type of regulated cell death (RCD), characterized by iron-dependent oxidative stress and the accumulation of lethal oxidized lipids. With a focus on the recent literature, the connection between iron homeostasis, oxidative stress and lipid metabolism is highlighted, which overall regulates ferroptotic cellular death. Moreover, special attention is devoted to the possible activation of this RCD pathway as a mechanism of tumor suppression. Its in-depth understanding from a regulatory and molecular perspective could provide important information for the development of new candidate drugs for the treatment of tumors resistant to conventional therapies. Based on the multifaceted molecular machinery that tightly controls iron cellular homeostasis, this review delves into its paradoxical, potentially dangerous role in biological systems, with a special focus on double-edged sword correlations with cancer. Indeed, though iron is a vital micronutrient and a required cofactor participating in several essential cell functions, its tendency to cause oxidative stress can be related both to cancer risk and to the activation of cancer cell death pathways. In this scenario, ferroptosis refers to an iron-dependent form of regulated cell death (RCD) powered by an overload of lethal peroxides sharing distinctive oxidized phospholipid profiles. As a unique cell death pathway, ferroptosis is both morphologically and mechanistically different from other types of programmed cell death involving executioner family proteins. The accumulation of cytotoxic lipid peroxides encompasses a cellular antagonism between ferroptosis execution and defense systems, with iron-dependent death occurring when ferroptosis-promoting activities significantly exceed the cellular antioxidant defenses. The most recent molecular breakthroughs in the execution of ferroptosis have aroused great consideration in tumor biology, as targeting ferroptosis can provide new tools for exploring therapeutic strategies for tumor suppression. Mutations and death/survival pathway alterations, as well as distinctive metabolic regulations of cancer cells, including the propensity to generate ROS, are seen as features that can render cancer cells unprotected to ferroptosis, thereby exposing vulnerabilities which deserve further attention to be regarded as targetable for cancers with limited therapeutic options. [ABSTRACT FROM AUTHOR]

Based on compelling preclinical evidence concerning the progress of our novel ruthenium-based metallotherapeutics, we are focusing research efforts on challenging indications for the treatment of invasive neoplasms such as the triple-negative breast cancer (TNBC). This malignancy mainly afflicts younger women, who are black, or who have a BRCA1 mutation. Because of faster growing and spreading, TNBC differs from other invasive breast cancers having fewer treatment options and worse prognosis, where existing therapies are mostly ineffective, resulting in a large unmet biomedical need. In this context, we benefited from an experimental model of TNBC both in vitro and in vivo to explore the effects of a biocompatible cationic liposomal nanoformulation, named HoThyRu/DOTAP, able to effectively deliver the antiproliferative ruthenium(III) complex AziRu, thus resulting in a prospective candidate drug. As part of the multitargeting mechanisms featuring metal-based therapeutics other than platinum-containing agents, we herein validate the potential of HoThyRu/DOTAP liposomes to act as a multimodal anticancer agent through inhibition of TNBC cell growth and proliferation, as well as migration and invasion. The here-obtained preclinical findings suggest a potential targeting of the complex pathways network controlling invasive and migratory cancer phenotypes. Overall, in the field of alternative chemotherapy to platinum-based drugs, these outcomes suggest prospective brand-new settings for the nanostructured AziRu complex to get promising goals for the treatment of metastatic TNBC. [ABSTRACT FROM AUTHOR]

To investigate how plants cope with multi-stress conditions, we analyzed the biochemical and molecular changes of Vitis vinifera leaves subjected to single or sequential double stresses (infection by Botrytis cinerea (Bc) and ozone (O3, 100 ppb for 3 h) treatment). In Bc+/O3− leaves, the hydrogen peroxide (H2O2) induction (observed at 12 and 24 h from the end of treatment (FET)) triggered a production of ethylene (Et; +35% compared with Bc−/O3− leaves), which was preceded by an increase of salicylic acid (SA; +45%). This result confirms a crosstalk between SA- and Et-related signaling pathways in lesion spread. The ozone induced an early synthesis of Et followed by jasmonic acid (JA) and SA production (about 2-fold higher), where Et and SA signaling triggered reactive oxygen species production by establishing a feedback loop, and JA attenuated this cycle by reducing Et biosynthesis. In Bc+ + O3+ leaves, Et peaked at 6 and 12 h FET, before SA confirmed a crosstalk between Et- and SA-related signaling pathways in lesion propagation. In O3+ + Bc+ leaves, the H2O2 induction triggered an accumulation of JA and Et, demonstrating a synergistic action in the regulation of defence reactions. The divergence in these profiles suggests a rather complex network of events in the transcriptional regulation of genes involved in the systemic acquired resistance. [ABSTRACT FROM AUTHOR]

The application of ozonated water in the vineyard is an increasingly popular tool for disease management, but the quality of grapes and resulting wines is likely to be affected. Endotherapy, or trunk injection, is a particularly useful method to apply phytosanitary products since many fungal pathogens colonize the grapevine woody tissues. Thus, the present study aimed to evaluate the effect on wine quality of the ozonated water applied to Bobal grapevines, one of the most cultivated red varieties in Spain, through endotherapy (E) or its combination with spraying (E + S). Endotherapy was carried out four times before harvest for both E and E + S treatments, and spraying was performed 2 days before and after each endotherapy application. Grapes were harvested, vinified, and the quality of the finished wines was evaluated through several enological parameters and the phenolic and volatile composition. Both treatments resulted in less alcoholic and more acidic wines. The E treatment, although it reduced the content of phenolic acids, stilbenes and flavanols, significantly increased anthocyanins, whereas E + S decreased the overall amount of phenolics, which had different implications for wine colour. In terms of aroma, both treatments, but E to a greater extent, reduced the content of glycosylated precursors and differentially affected free volatiles, both varietal and fermentative. Thus, the dose of ozonated water, frequency and/or method of application are determining factors in the effect of these treatments on wine quality and must be carefully considered by winegrowers to establish the optimum treatment conditions so as not to impair the quality of wines. [ABSTRACT FROM AUTHOR]

Countless expectations converge in the multidisciplinary endeavour for the search and development of effective and safe drugs in fighting cancer. Although they still embody a minority of the pharmacological agents currently in clinical use, metal-based complexes have great yet unexplored potential, which probably hides forthcoming anticancer drugs. Following the historical success of cisplatin and congeners, but also taking advantage of conventional chemotherapy limitations that emerged with applications in the clinic, the design and development of non-platinum metal-based chemotherapeutics, either as drugs or prodrugs, represents a rapidly evolving field wherein candidate compounds can be fine-tuned to access interactions with druggable biological targets. Moving in this direction, over the last few decades platinum family metals, e.g., ruthenium and palladium, have been largely proposed. Indeed, transition metals and molecular platforms where they originate are endowed with unique chemical and biological features based on, but not limited to, redox activity and coordination geometries, as well as ligand selection (including their inherent reactivity and bioactivity). Herein, current applications and progress in metal-based chemoth are reviewed. Converging on the recent literature, new attractive chemotherapeutics based on transition metals other than platinum—and their bioactivity and mechanisms of action—are examined and discussed. A special focus is committed to anticancer agents based on ruthenium, palladium, rhodium, and iridium, but also to gold derivatives, for which more experimental data are nowadays available. Next to platinum-based agents, ruthenium-based candidate drugs were the first to reach the stage of clinical evaluation in humans, opening new scenarios for the development of alternative chemotherapeutic options to treat cancer. [ABSTRACT FROM AUTHOR]

Chemical analysis of the Mediterranean ascidian Polyandrocarpa zorritensis (Van Name 1931) resulted in the isolation of a series of molecules including two monoindole alkaloids, 3-indolylglyoxylic acid (3) and its methyl ester (4), 4-hydroxy-3-methoxyphenylglyoxylic acid methyl ester (1) and a new alkaloid we named zorrimidazolone (2). The structure of the novel compound 2 has been elucidated by spectroscopic analysis and bioactivity of all compounds has been investigated. Zorrimidazolone (2) showed a modest cytotoxic activity against C6 rat glioma cell line. [ABSTRACT FROM AUTHOR]

Ozone is widely used in the agri-food and food processing industries mainly as a sanitizing agent. However, it has recently become clear that ozone exposition leads to another important benefit: in living tissues, the induced-oxidative stress triggers the antioxidant response, and, therefore, it enhances the production of antioxidant and stress-related secondary metabolites. As such, ozone can be considered an abiotic elicitor. The goal of the present review was to critically summarize knowledge about the possibility of improving bioactive compounds and, consequently, the health-related properties of grapes and wine, by using ozone. The greatest interest has been given not only to the pre- and post-harvest treatment of table and wine grapes, but also to the explanation of the mechanisms involved in the ozone-related response and the main secondary metabolites biosynthetic pathways. From the literature available, it is clear that the effect of ozone treatment on health-related properties and secondary metabolites accumulation depends on many factors, such as the cultivar, but also the form (water or gaseous), doses, and application method of ozone. Most of the published papers report an increase in antioxidant compounds (e.g., polyphenols) and stress-related volatiles, confirming the hypothesis that ozone could be used to improve berry and wine compositional and sensory quality. [ABSTRACT FROM AUTHOR]

Simple Summary: The availability of selective, effective, and safe anticancer agents is a major challenge in the field of cancer research. As part of a multidisciplinary research project, in recent years our group has proposed an original class of nanomaterials for the delivery of new anticancer drugs based on ruthenium(III) complexes. In cellular models, these nanosystems have been shown to be effective in counteracting growth and proliferation of human breast cancer cells. Compared to conventional metallochemotherapeutics such as platinum-based agents whose clinical practice is associated with serious undesirable effects, ruthenium complexes share improved biochemical profiles making them more selective towards cancer cells and less cytotoxic to healthy cells. Their combination with biocompatible nanocarriers further enhances these promising features, as here showcased by our research carried out in an animal model which underscores the efficacy and safety in vivo of one of our most promising ruthenium-based nanosystems. Selectivity and efficacy towards target cancer cells, as well as biocompatibility, are current challenges of advanced chemotherapy powering the discovery of unconventional metal-based drugs and the search for novel therapeutic approaches. Among second-generation metal-based chemotherapeutics, ruthenium complexes have demonstrated promising anticancer activity coupled to minimal toxicity profiles and peculiar biochemical features. In this context, our research group has recently focused on a bioactive Ru(III) complex—named AziRu—incorporated into a suite of ad hoc designed nucleolipid nanosystems to ensure its chemical stability and delivery. Indeed, we proved that the structure and properties of decorated nucleolipids can have a major impact on the anticancer activity of the ruthenium core. Moving in this direction, here we describe a preclinical study performed by a mouse xenograft model of human breast cancer to establish safety and efficacy in vivo of a cationic Ru(III)-based nucleolipid formulation, named HoThyRu/DOTAP, endowed with superior antiproliferative activity. The results show a remarkable reduction in tumour with no evidence of animal suffering. Blood diagnostics, as well as biochemical analysis in both acute and chronic treated animal groups, demonstrate a good tolerability profile at the therapeutic regimen, with 100% of mice survival and no indication of toxicity. In addition, ruthenium plasma concentration analysis and tissue bioaccumulation were determined via appropriate sampling and ICP-MS analysis. Overall, this study supports both the efficacy of our Ru-containing nanosystem versus a human breast cancer model and its safety in vivo through well-tolerated animal biological responses, envisaging a possible forthcoming use in clinical trials. [ABSTRACT FROM AUTHOR]

Phenolic compounds, the most widely distributed class of natural products in the plants, show several biological properties including antifungal activity. Phenolics contained in grapes can be classified in two main groups, flavonoids and non-flavonoids compounds. Variability and yield extraction of phenolic and polyphenolic compounds from different matrices of Vitis vinifera depends of cultivar, climate, soil condition and process technology. Unripe grapes, berry skins and seeds, leaves, canes and stems and not-fermented and fermented pomaces represent large reusable and valuable wastes from agricultural and agro-industrial processes. This review summarizes studies that examine the extraction method, chemical characterization, and antifungal activity of phenolic and polyphenolic compounds from edible and non-edible V. vinifera matrices against human fungal pathogens. In the world, around one billion people have fungal diseases related to skin, nail or hair and around 150 million have systemic diseases caused by fungi. Few studies on antifungal activity of plant extracts have been performed. This review provides useful information for the application of V. vinifera phenolics in the field of antifungals for human use. [ABSTRACT FROM AUTHOR]

In this review we have showcased the preclinical development of original amphiphilic nanomaterials designed for ruthenium-based anticancer treatments, to be placed within the current metallodrugs approach leading over the past decade to advanced multitarget agents endowed with limited toxicity and resistance. This strategy could allow for new options for breast cancer (BC) interventions, including the triple-negative subtype (TNBC) with poor therapeutic alternatives. BC is currently the second most widespread cancer and the primary cause of cancer death in women. Hence, the availability of novel chemotherapeutic weapons is a basic requirement to fight BC subtypes. Anticancer drugs based on ruthenium are among the most explored and advanced next-generation metallotherapeutics, with NAMI-A and KP1019 as two iconic ruthenium complexes having undergone clinical trials. In addition, many nanomaterial Ru complexes have been recently conceived and developed into anticancer drugs demonstrating attractive properties. In this field, we focused on the evaluation of a Ru(III) complex—named AziRu—incorporated into a suite of both zwitterionic and cationic nucleolipid nanosystems, which proved to be very effective for the in vivo targeting of breast cancer cells (BBC). Mechanisms of action have been widely explored in the context of preclinical evaluations in vitro, highlighting a multitarget action on cell death pathways which are typically deregulated in neoplasms onset and progression. Moreover, being AziRu inspired by the well-known NAMI-A complex, information on non-nanostructured Ru-based anticancer agents have been included in a precise manner. [ABSTRACT FROM AUTHOR]

Hair disorders may considerably impact the social and psychological well-being of an individual. Recent advances in the understanding the biology of hair have encouraged the research and development of novel and safer natural hair growth agents. In this context, we have previously demonstrated—at both preclinical and clinical level—that an Annurca apple-based dietary supplement (AMS), acting as a nutraceutical, is endowed with an intense hair-inductive activity (trichogenicity), at once increasing hair tropism and keratin content. Herein, in the framework of preclinical investigations, new experiments in primary human models of follicular keratinocytes and dermal papilla cells have been performed to give an insight around AMS biological effects on specific hair keratins expression. As well as confirming the biocompatibility and the antioxidant proprieties of our nutraceutical formulation, we have proven an engagement of trichokeratins production underlying its biological effects on human follicular cells. Annurca apples are particularly rich in oligomeric procyanidins, natural polyphenols belonging to the broader class of bioflavonoids believed to exert many beneficial health effects. To our knowledge, none of the current available remedies for hair loss has hitherto shown to stimulate the production of hair keratins so clearly. [ABSTRACT FROM AUTHOR]