Inflammation represents a very frequent condition in humans; it is often underestimated, making the problem an increasingly alarming phenomenon. For these reasons, conventional therapies are losing...

Inflammation represents an adaptive response generated by injuries or harmful stimuli. Natural remedies represent an interesting alternative to traditional therapies, involving several biochemical pathways. Besides, the valorization of agrochemical wastes nowadays seems to be a feasible way to reduce the health spending and improve the accessibility at bioactive natural compounds. In this context, the chemical composition of three Glycyrrhiza glabra L. (licorice) leaf extracts, obtained through maceration or ultrasound-assisted method (fresh and dried leaves) was investigated. A guided fractionation obtained three main components: pinocembrin, glabranin and licoflavanone. All the extracts showed similar antioxidant properties, evaluated by 2,2′-diphenyl-1-picrylhydrazyl (DPPH) or 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) Diammonium Salt (ABTS) assay, while, among the isolated compounds, licoflavanone exhibited the best antioxidant activity. The anti-inflammatory activity of the extracts and the purified compounds was investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. Extract C and licoflavanone showed a good anti-inflammatory activity without affecting cell viability, as they decreased nitrite levels even when used at 12.5 μg/mL (p < 0.005) and 50 μM concentration (p < 0.001), respectively. Interestingly, licoflavanone markedly decreased pro-inflammatory cytokines and cyclooxygenase 2/inducible nitric oxide synthase (COX-2/iNOS) expression levels (p < 0.001). A modulation of nuclear factor kappa B/mitogen-activated protein kinases (NF-kB/MAPK) pathway underlay such behavior, highlighting the potential of this natural compound as a new scaffold in anti-inflammatory drug research.

The rational discovery of new specialized metabolites by genome mining represents a very promising strategy in the quest for new bioactive molecules. Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural product that derive from genetically encoded precursor peptides. However, RiPP gene clusters are particularly refractory to reliable bioinformatic predictions due to the absence of a common biosynthetic feature across all pathways. Here, we describe RiPPER, a new tool for the family-independent identification of RiPP precursor peptides and apply this methodology to search for novel thioamidated RiPPs in Actinobacteria. Until now, thioamidation was believed to be a rare post-translational modification, which is catalyzed by a pair of proteins (YcaO and TfuA) in Archaea. In Actinobacteria, the thioviridamide-like molecules are a family of cytotoxic RiPPs that feature multiple thioamides, which are proposed to be introduced by YcaO-TfuA proteins. Using RiPPER, we show that previously undescribed RiPP gene clusters encoding YcaO and TfuA proteins are widespread in Actinobacteria and encode a highly diverse landscape of precursor peptides that are predicted to make thioamidated RiPPs. To illustrate this strategy, we describe the first rational discovery of a new structural class of thioamidated natural products, the thiovarsolins from Streptomyces varsoviensis.

Thioviridamide is a structurally novel ribosomally synthesized and post-translational modified peptide (RiPP) produced by Streptomyces olivoviridis NA005001. It is characterized by a structure that features a series of thioamide groups and possesses potent antiproliferative activity in cancer cell lines. Its unusual structure allied to its promise as an anticancer compound led us to investigate the diversity of thioviridamide-like pathways across sequenced bacterial genomes. We have isolated and characterized three diverse members of this family of natural products. This characterization is supported by transformation-associated recombination cloning and heterologous expression of one of these compounds, thiostreptamide S4. Our work provides an insight into the diversity of this rare class of compound and indicates that the unusual N-terminus of thioviridamide is not introduced biosynthetically but is instead introduced during acetone extraction. A detailed analysis of the biological activity of one of the newly discovered compounds, thioalbamide, indicates that it is highly cytotoxic to cancer cells, while exhibiting significantly less activity toward a noncancerous epithelial cell line.

Metabolic reprogramming is a hallmark of cancer, which implements a profound metabolic rewiring in order to support a high proliferation rate and to ensure cell survival in its complex microenvironment. Although initial studies considered glycolysis as a crucial metabolic pathway in tumor metabolism reprogramming (i.e., the Warburg effect), recently, the critical role of mitochondria in oncogenesis, tumor progression, and neoplastic dissemination has emerged. In this report, we examined the main mitochondrial metabolic pathways that are altered in cancer, which play key roles in the different stages of tumor progression. Furthermore, we reviewed the function of important molecules inhibiting the main mitochondrial metabolic processes, which have been proven to be promising anticancer candidates in recent years. In particular, inhibitors of oxidative phosphorylation (OXPHOS), heme flux, the tricarboxylic acid cycle (TCA), glutaminolysis, mitochondrial dynamics, and biogenesis are discussed. The examined mitochondrial metabolic network inhibitors have produced interesting results in both preclinical and clinical studies, advancing cancer research and emphasizing that mitochondrial targeting may represent an effective anticancer strategy.

Breast cancer is the second greatest cause of cancer-related death in women. Resistance to endocrine treatments or chemotherapy is a limiting drawback. In this context, this work aims to evaluate the effects of cholesterol and mevalonate during tumor progression and their contribution in the onset of resistance to clinical treatments in use today. In this study, we demonstrated that cholesterol and mevalonate treatments were able to activate the estrogen-related receptor alpha (ERRα) pathway, increasing the expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ERbB2/human epithelial receptor (HER2), tumor protein D52 (TPD52), and NOTCH2 proteins in breast cancer cells. The activation of this pathway is shown to be responsible for intense metabolic switching, higher proliferation rates, sustained motility, the propagation of cancer stem-like cells (CSCs), and lipid droplet formation. All of these events are related to greater tumor propagation, aggressiveness, and drug resistance. Furthermore, the activation and expression of proteins induced by the treatment with cholesterol or mevalonate are consistent with those obtained from the MCF-7/TAMr cell line, which is largely used as a breast cancer model of acquired endocrine therapy resistance. Altogether, our data indicate that cholesterol and mevalonate are two metabolites implicated in breast cancer progression, aggressiveness, and drug resistance, through the activation of the ERRα pathway. Our findings enable us to identify the ERRα receptor as a poor prognostic marker in patients with breast carcinoma, suggesting the correlation between cholesterol/mevalonate and ERRα as a new possible target in breast cancer treatment.