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Abstract BH3 mimetics, targeting the Bcl-2 family anti-apoptotic proteins, represent a promising therapeutic opportunity in cancers. ABT-199, the first specific Bcl-2 inhibitor, was approved by FDA for the treatment of several hematological malignancies. We have recently discovered IS21, a novel pan BH3 mimetic with preclinical antitumor activity in several tumor types. Here, we evaluated the efficacy of IS21 and other BH3 mimetics, both as single agents and combined with the currently used antineoplastic agents in T-cell acute lymphoblastic leukemia, ovarian cancer, and melanoma. IS21 was found to be active in T-cell acute lymphoblastic leukemia, melanoma, lung, pancreatic, and ovarian cancer cell lines. Bcl-xL and Mcl-1 protein levels predicted IS21 sensitivity in melanoma and ovarian cancer, respectively. Exploring IS21 mechanism of action, we found that IS21 activity depends on the presence of BAX and BAK proteins: complexes between Bcl-2 and Bcl-xL proteins and their main binding partners were reduced after IS21 treatment. In combination experiments, BH3 mimetics sensitized leukemia cells to chemotherapy, ovarian cancer cells and melanoma models to PARP and MAPK inhibitors, respectively. We showed that this enhancing effect was related to the potentiation of the apoptotic pathway, both in hematologic and solid tumors. In conclusion, our data suggest the use of inhibitors of anti-apoptotic proteins as a therapeutic strategy to enhance the efficacy of anticancer treatment.

Plants of genus Cichorium (Asteraceae) can be used as vegetables with higher nutritional value and as medicinal plants. This genus has beneficial properties owing to the presence of a number of specialized metabolites such as alkaloids, sesquiterpene lactones, coumarins, unsaturated fatty acids, flavonoids, saponins, and tannins. Cichorium endivia L., known as escarole, has achieved a common food status due to its nutritionary value, bitter taste, and the presence of healthy components, and is eaten cooked or raw in salads. Presently, wastes derived from the horticultural crops supply chain are generated in very large amounts. Vegetable waste comprises the discarded leaves of food sources produced during collection, handling, transportation, and processing. The external leaves of Cichorium endivia L. are a horticultural crop that is discarded. In this work, the phytochemical profile, antioxidant, and anti-inflammatory activities of hydroalcoholic extract obtained from discarded leaves of three cultivars of escarole (C. endivia var. crispum ‘Capriccio’, C. endivia var. latifolium ‘Performance’ and ‘Leonida’) typical horticultural crop of the Campania region were investigated. In order to describe a metabolite profile of C. endivia cultivars, the extracts were analysed by HR/ESI/Qexactive/MS/MS and NMR. The careful analysis of the accurate masses, the ESI/MS spectra, and the 1H NMR chemical shifts allowed for the identification of small molecules belonging to phenolic, flavonoid, sesquiterpene, amino acids, and unsaturated fatty acid classes. In addition, the antioxidant potential of the extracts was evaluated using cell-free and cell-based assays, as well as their cytotoxic and anti-inflammatory activity. All the extracts showed similar radical-scavenging ability while significant differences between the three investigated cultivars emerged in the cell-based assays. The obtained data were ascribed to the content of polyphenols and sesquiterpenes in the extracts. Accordingly, C. endivia by-products can be deemed an interesting material for healthy product formulations.

Premna, a genus consisting of approximately 200 species, predominantly thrives in tropical and subtropical areas. Many of these species have been utilized in ethnopharmacology for diverse medicinal applications. In Saudi Arabia, Premna resinosa (Hochst.) Schauer (Lamiaceae) grows wildly, and its slightly viscid leaves are attributed to the production of leaf accession. In this study, we aimed to extract the surface accession from fresh leaves using dichloromethane to evaluate the anticancer potential. The plant exudate yielded two previously unknown labdane diterpenes, Premnaresone A and B, in addition to three already described congeners and four known flavonoids. The isolation process was accomplished using a combination of silica gel column chromatography and semi-preparative HPLC, the structures of which were identified by NMR and HRESIMS analyses and a comparison with the literature data of associated compounds. Furthermore, we employed a density functional theory (DFT)/NMR approach to suggest the relative configuration of different compounds. Consequently, we investigated the possibility of developing new chaperone inhibitors by subjecting diterpenes 1–5 to a Surface Plasmon Resonance-screening, based on the knowledge that oridonin, a diterpene, interacts with Heat Shock Protein 70 (Hsp70) 1A in cancer cells. Additionally, we studied the anti-proliferative activity of compounds 1–5 on human Jurkat (human T-cell lymphoma) and HeLa (epithelial carcinoma) cell lines, where diterpene 3 exhibited activity in Jurkat cell lines after 48 h, with an IC50 of 15.21 ± 1.0 µM. Molecular docking and dynamic simulations revealed a robust interaction between compound 3 and Hsp70 key residues.

Chronic venous disease (CVD) is an often underestimated inflammatory pathological condition that can have a serious impact on quality of life. Many therapies have been proposed to deal with CVD, but unfortunately the symptoms recur with increasing frequency and intensity as soon as treatments are stopped. Previous studies have shown that the common inflammatory transcription factor AP-1 (activator protein-1) and nuclear factor kappa-activated B-cell light chain enhancer (NF-kB) play key roles in the initiation and progression of this vascular dysfunction. The aim of this research was to develop a herbal product that acts simultaneously on different aspects of CVD-related inflammation. Based on the evidence that several natural components of plant origin are used to treat venous insufficiency and that magnolol has been suggested as a putative modulator of AP-1, two herbal preparations based on Ruscus aculeatus root extracts, and Vitis vinifera seed extracts, as well as diosmetin and magnolol, were established. A preliminary MTT-based evaluation of the possible cytotoxic effects of these preparations led to the selection of one of them, named DMRV-2, for further investigation. First, the anti-inflammatory efficacy of DMRV-2 was demonstrated by monitoring its ability to reduce cytokine secretion from endothelial cells subjected to LPS-induced inflammation. Furthermore, using a real-time PCR-based protocol, the effect of DMRV-2 on AP-1 expression and activity was also evaluated; the results obtained demonstrated that the incubation of the endothelial cells with this preparation almost completely nullified the effects exerted by the treatment with LPS on AP-1. Similar results were also obtained for NF-kB, whose activation was evaluated by monitoring its distribution between the cytosol and the nucleus of endothelial cells after the different treatments.

A comparative quali-quantitative study of the peel extracts of eight Punica granatum cultivars obtained from underexploited areas of South Italy was carried out in order to valorize them as health-promoting by-products. The results showed that all of the samples possessed 45 ellagitannins, consisting mainly of polyhydroxyphenoyls; 10 flavonoids, belonging to flavonol, flavone, and catechin classes; and 2 anthocyanins. The most representative compounds underwent quantification through a LC-MS/MS multiple reaction monitoring (MRM)-based method; their qualitative profile was almost superimposable, while variability in the quantitative phenolic content was observed. The antioxidant activity was investigated using cell-free and cell-based assays. The in vitro anti-inflammatory potential was also studied by monitoring three typical markers of inflammation (IL-1β, IL-6, and TNF-α). Moderate differences in both activities were observed between the cultivars. Results showed that all of the investigated peels have a potential use as healthy bioactive phytocomplexes due to the interesting antioxidant and anti-inflammatory activities; in particular from the bioinformatic approaches a series of compounds, including galloyl-, pedunculagin- and ellagic acid-based, were found to be highly correlated with bioactivity of the extracts. Finally, the bioactivities showed by a Campanian local cultivar, ‘Granato di Aiello del Sabato’, could promote its cultivation by local farmers and germplasm conservation.

Flavonoids are among the most abundant natural bioactive compounds produced by plants. Many different activities have been reported for these secondary metabolites against numerous cells and systems. One of the most interesting is certainly the antimicrobial, which is stimulated through various molecular mechanisms. In fact, flavonoids are effective both in directly damaging the envelope of Gram-negative and Gram-positive bacteria but also by acting toward specific molecular targets essential for the survival of these microorganisms. The purpose of this paper is to present an overview of the most interesting results obtained in the research focused on the study of the interactions between flavonoids and bacterial proteins. Despite the great structural heterogeneity of these plant metabolites, it is interesting to observe that many flavonoids affect the same cellular pathways. Furthermore, it is evident that some of these compounds interact with more than one target, producing multiple effects. Taken together, the reported data demonstrate the great potential of flavonoids in developing innovative systems, which can help address the increasingly serious problem of antibiotic resistance.