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In the early stages of carcinogenesis, the transformed cells become “invisible” to the immune system. From this moment on, the evolution of the tumor depends essentially on the genotype of the primitive cancer cells and their subsequent genetic drift. The role of the immune system in blocking tumor progression from the earliest stages is largely underestimated because by the time tumors are clinically detectable, the immune system has already completely failed its task. Therefore, a clinical treatment capable of restoring the natural anti-tumor role of the immune system could prove to be the “ultimate weapon” against cancer. Herein, we propose a novel therapeutic approach for the treatment of solid cancer that exploits the capability of activated monocytes to transfer major histocompatibility complex I (MHC-I) molecules bound to antigenic peptides to cancer cells using microvesicles as cargo, making tumor cells target of a “natural” CD8+ T lymphocyte cytotoxic response.

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by impaired glucose homeostasis and serious long-term complications. First-line therapeutic options for T2DM treatment are monodrug therapies, often replaced by multidrug therapies to ensure that non-responding patients maintain target glycemia levels. The use of multitarget drugs instead of mono- or multidrug therapies has been emerging as a main strategy to treat multifactorial diseases, including T2DM. Therefore, modern drug discovery in its early stages aims to identify potential modulators for multiple targets; for this purpose, exploration of the chemical space of natural products represents a powerful tool. Our study demonstrates that avarone, a sesquiterpene quinone obtained from the sponge Dysidea avara, is capable of inhibiting in vitro PTP1B, the main negative regulator of the insulin receptor, while it improves insulin sensitivity, and mitochondria activity in C2C12 cells. We observe that when avarone is administered alone, it acts as an insulin-mimetic agent. In addition, we show that avarone acts as a tight binding inhibitor of aldose reductase (AKR1B1), the enzyme involved in the development of diabetic complications. Overall, avarone could be proposed as a novel natural hit to be developed as a multitarget drug for diabetes and its pathological complications.

Diabetes mellitus (DM) represents a complex and multifactorial disease that causes metabolic disorders with acute and long-term serious complications. The onset of DM, with over 90% of cases of diabetes classified as type 2, implies several metabolic dysfunctions leading to consider DM a worldwide health problem. In this frame, protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) are two emerging targets involved in the development of type 2 diabetes mellitus (T2DM) and its chronic complications. Herein, we employed a marine-derived dual type inhibitor of these enzymes, phosphoeleganin, as chemical starting point to perform a fragment-based process in search for new inhibitors. Phosphoeleganin was both disassembled by its oxidative cleavage and used as model structure for the synthesis of a small library of functionalized derivatives as rationally designed analogues. Pharmacological screening supported by in silico docking analysis outlined the mechanism of action against PTP1B exerted by a phosphorylated fragment and a synthetic simplified analogue, which represent the most potent inhibitors in the library.

The chemical investigation of the Mediterranean ascidian Clavelina lepadiformis has led to the isolation of a new lepadin, named lepadin L, and two known metabolites belonging to the same family, lepadins A and B. The planar structure and relative configuration of the decahydroquinoline ring of lepadin L were established both by means of HR-ESIMS and by a detailed as extensive analysis of 1D and 2D NMR spectra. Moreover, microscale derivatization of the new alkaloid lepadin L was performed to assess the relative configuration of the functionalized alkyl side chain. Lepadins A, B, and L were tested for their cytotoxic activity on a panel of cancer cell lines (human melanoma [A375], human breast [MDA-MB-468], human colon adenocarcinoma [HT29], human colorectal carcinoma [HCT116], and mouse myoblast [C2C12]). Interestingly, a deeper investigation into the mechanism of action of the most cytotoxic metabolite, lepadin A, on the A375 cells has highlighted its ability to induce a strongly inhibition of cell migration, G2/M phase cell cycle arrest and a dose-dependent decrease of cell clonogenity, suggesting that it is able to impair self-renewing capacity of A375 cells.

An in-depth study on the inhibitory mechanism on protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes, including analysis of the insulin signalling pathway, of phosphoeleganin, a marine-derived phosphorylated polyketide, was achieved. Phosphoeleganin was demonstrated to inhibit both enzymes, acting respectively as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, in silico docking analyses to evaluate the interaction mode of phosphoeleganin with both enzymes were performed. Interestingly, this study showed that phosphoeleganin is the first example of a dual inhibitor polyketide extracted from a marine invertebrate, and it could be used as a versatile scaffold structure for the synthesis of new designed multiple ligands.

Diabetes mellitus (DM) represents a group of metabolic disorders that leads to acute and long-term serious complications and is considered a worldwide sanitary emergence. Type 2 diabetes (T2D) represents about 90% of all cases of diabetes, and even if several drugs are actually available for its treatment, in the long term, they show limited effectiveness. Most traditional drugs are designed to act on a specific biological target, but the complexity of the current pathologies has demonstrated that molecules hitting more than one target may be safer and more effective. The purpose of this review is to shed light on the natural compounds known as α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) dual-inhibitors that could be used as lead compounds to generate new multitarget antidiabetic drugs for treatment of T2D.

Zinc environmental levels are increasing due to human activities, posing a threat to ecosystems and human health. Therefore, new tools able to remediate Zn contamination in freshwater are highly recommended. Specimens of Dreissena polymorpha (zebra mussel) were exposed for 48 h and 7 days to a wide range of ZnCl2 nominal concentrations (1–10–50–100 mg/L), including those environmentally relevant. Cellulose-based nanosponges (CNS) were also tested to assess their safety and suitability for Zn removal from freshwater. Zebra mussels were exposed to 50 mg/L ZnCl2 alone or incubated with 1.25 g/L of CNS (2 h) and then removed by filtration. The effect of Zn decontamination induced by CNS has been verified by the acute toxicity bioassay Microtox®. DNA primary damage was investigated by the Comet assay; micronuclei frequency and nuclear morphological alterations were assessed by Cytome assay in mussels’ haemocytes. The results confirmed the genotoxic effect of ZnCl2 in zebra mussel haemocytes at 48 h and 7-day exposure time. Zinc concentrations were measured in CNS, suggesting that cellulose-based nanosponges were able to remove Zn(II) by reducing its levels in exposure waters and soft tissues of D. polymorpha in agreement with the observed restoration of genetic damage exerted by zinc exposure alone.

Benzo(a)pyrene (B(a)P) is a well-known genotoxic agent, the removal of which from environmental matrices is mandatory, necessitating the application of cleaning strategies that are harmless to human and environmental health. The potential application of nanoparticles (NPs) in the remediation of polluted environments is of increasing interest. Here, specifically designed NPs were selected as being non-genotoxic and able to interact with B(a)P, in order to address the genetic and chromosomal damage it produces. A newly formulated pure anatase nano-titanium (nano-TiO2), a commercial mixture of rutile and anatase, and carbon black-derived hydrophilic NPs (HNP) were applied. Once it had been ascertained that the NPs selected for the work did not induce genotoxicity, marine mussel gill biopsies were exposed in vitro to B(a)P (2 μg/mL), alone and in combination with the selected NPs (50 µg/mL nano-TiO2, 10 µg/mL HNP). DNA primary reversible damage was evaluated by means of the Comet assay. Chromosomal persistent damage was assessed on the basis of micronuclei frequency and nuclear abnormalities by means of the Micronucleus-Cytome assay. Transmission Electron Microscopy (TEM) was performed to investigate the mechanism of action exerted by NPs. Pure Anatase n-TiO2 was found to be the most suitable for our purpose, as it is cyto- and genotoxicity free and able to reduce the genetic and chromosomal damage associated with exposure to B(a)P.

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.

The contamination of freshwaters by heavy metals represents a great problem, posing a threat for human and environmental health. Cadmium is classified as carcinogen to humans and its mechanism of carcinogenicity includes genotoxic events. In this study a recently developed eco-friendly cellulose-based nanosponge (CNS) was investigated as a candidate in freshwater nano-remediation process. For this purpose, CdCl2 (0.05 mg L−1) contaminated artificial freshwater (AFW) was treated with CNS (1.25 g L−1 for 2 h), and cellular responses were analyzed before and after CNS treatment in Dreissena polymorpha hemocytes. A control group (AFW) and a negative control group (CNS in AFW) were also tested. DNA primary damage was evaluated by Comet assay while chromosomal damage and cell proliferation were assessed by Cytome assay. AFW exposed to CNS did not cause any genotoxic effect in zebra mussel hemocytes. Moreover, DNA damage and cell proliferation induced by Cd(II) turned down to control level after 2 days when CNS were used. A reduction of Cd(II)-induced micronuclei and nuclear abnormalities was also observed. CNS was thus found to be a safe and effective candidate in cadmium remediation process being efficient in metal sequestering, restoring cellular damage exerted by Cd(II) exposure, without altering cellular physiological activity.

To encourage the applicability of nano-adsorbent materials for heavy metal ion removal from seawater and limit any potential side effects for marine organisms, an ecotoxicological evaluation based on a biological effect-based approach is presented. ZnCl2 (10 mg L−1) contaminated artificial seawater (ASW) was treated with newly developed eco-friendly cellulose-based nanosponges (CNS) (1.25 g L−1 for 2 h), and the cellular and tissue responses of marine mussel Mytilus galloprovincialis were measured before and after CNS treatment. A control group (ASW only) and a negative control group (CNS in ASW) were also tested. Methods: A significant recovery of Zn-induced damages in circulating immune and gill cells and mantle edges was observed in mussels exposed after CNS treatment. Genetic and chromosomal damages reversed to control levels in mussels’ gill cells (DNA integrity level, nuclear abnormalities and apoptotic cells) and hemocytes (micronuclei), in which a recovery of lysosomal membrane stability (LMS) was also observed. Damage to syphons, loss of cilia by mantle edge epithelial cells and an increase in mucous cells in ZnCl2-exposed mussels were absent in specimens after CNS treatment, in which the mantle histology resembled that of the controls. No effects were observed in mussels exposed to CNS alone. As further proof of CNS’ ability to remove Zn(II) from ASW, a significant reduction of >90% of Zn levels in ASW after CNS treatment was observed (from 6.006 to 0.510 mg L−1). Ecotoxicological evaluation confirmed the ability of CNS to remove Zn from ASW by showing a full recovery of Zn-induced toxicological responses to the levels of mussels exposed to ASW only (controls). An effect-based approach was thus proven to be useful in order to further support the environmentally safe (ecosafety) application of CNS for heavy metal removal from seawater.