Stevia rebaudiana Bertoni is a perennial shrub from Paraguay that is nowadays widely cultivated, since it is increasingly being utilized as a sugar substitute in various foodstuffs due to its sweetness and minimal caloric content. These properties of the plant’s derivatives have spurred research on their biological activities revealing a multitude of benefits to human health, including antidiabetic, anticariogenic, antioxidant, hypotensive, antihypertensive, antimicrobial, anti-inflammatory and antitumor actions. To our knowledge, no recent reviews have surveyed and reported published work solely on the latter. Consequently, our main objective was to present a concise, literature-based review of the biological actions of stevia derivatives in various tumor types, as studied in in vitro and in vivo models of the disease. With global cancer estimates suggesting a 47% increase in cancer cases by 2040 compared to 2020, the data reviewed in this article should provide a better insight into Stevia rebaudiana and its products as a means of cancer prevention and therapy within the context of a healthy diet.

Cancer stem cells (CSCs), a subpopulation of tumor cells with self-renewal capacity, have been associated with tumor initiation, progression, and therapy resistance. While the bulk of tumor cells mainly use glycolysis for energy production, CSCs have gained attention for their ability to switch between glycolysis and oxidative phosphorylation, depending on their energy needs and stimuli from their microenvironment. This metabolic plasticity is mediated by signaling pathways that are also implicated in the regulation of CSC properties, such as the Wnt/β-catenin, Notch, and Hippo networks. Two other stemness-associated processes, autophagy and hypoxia, seem to play a role in the metabolic switching of CSCs as well. Importantly, accumulating evidence has linked the metabolic plasticity of CSCs to their increased resistance to treatment. In this review, we summarize the metabolic signatures of CSCs and the pathways that regulate them; we especially highlight research data that demonstrate the metabolic adaptability of these cells and their role in stemness and therapy resistance. As the development of drug resistance is a major challenge for successful cancer treatment, the potential of specific elimination of CSCs through targeting their metabolism is of great interest and it is particularly examined.

Factor Xa (FXa) is the key serine protease of the coagulation cascade as it is the point of convergence of the intrinsic and extrinsic pathways, leading to the formation of thrombin. Factor Xa is an established target of anticoagulation therapy, due to its central role in coagulation. Over the past years, several direct oral anticoagulants (DOACs) targeting FXa have been developed. Rivaroxaban, apixaban, and edoxaban are used in clinical practice for prevention and treatment of thrombotic diseases. Increasing evidence suggests that FXa exerts nonhemostatic cellular effects that are mediated mainly through protease-activated receptors-1 and -2 and are involved in pathophysiological conditions, such as atherosclerosis, inflammation, and fibrosis. Direct inhibition of FXa by DOACs could be beneficial in these conditions. This is a narrative review that focuses on the cellular effects of FXa in various cell types and conditions, as well as on the possible pleiotropic effects of FXa-targeting DOACs.

Background: Type 2 diabetes mellitus is a risk factor for lower extremity arterial disease. Cilostazol expresses antiplatelet, anti‐inflammatory, and vasodilator actions and improves the claudication intermittent symptoms. We investigated the efficacy and safety of adjunctive cilostazol to clopidogrel‐treated patients with type 2 diabetes mellitus exhibiting symptomatic lower extremity arterial disease, in the prevention of ischemic vascular events and improvement of the claudication intermittent symptoms. Methods and Results: In a prospective 2‐arm, multicenter, open‐label, phase 4 trial, patients with type 2 diabetes mellitus with intermittent claudication receiving clopidogrel (75 mg/d) for at least 6 months, were randomly assigned in a 1:1 ratio, either to continue to clopidogrel monotherapy, without receiving placebo cilostazol (391 patients), or to additionally receive cilostazol, 100 mg twice/day (403 patients). The median duration of follow‐up was 27 months. The primary efficacy end point, the composite of acute ischemic stroke/transient ischemic attack, acute myocardial infarction, and death from vascular causes, was significantly reduced in patients receiving adjunctive cilostazol compared with the clopidogrel monotherapy group (sex‐adjusted hazard ratio [HR], 0.468; 95% CI, 0.252–0.870; P =0.016). Adjunctive cilostazol also significantly reduced the stroke/transient ischemic attack events (sex‐adjusted HR, 0.38; 95% CI, 0.15–0.98; P =0.046) and improved the ankle‐brachial index and pain‐free walking distance values ( P =0.001 for both comparisons). No significant difference in the bleeding events, as defined by Bleeding Academic Research Consortium criteria, was found between the 2 groups (sex‐adjusted HR, 1.080; 95% CI, 0.579–2.015; P =0.809). Conclusions: Adjunctive cilostazol to clopidogrel‐treated patients with type 2 diabetes mellitus with symptomatic lower extremity arterial disease may lower the risk of ischemic events and improve intermittent claudication symptoms, without increasing the bleeding risk, compared with clopidogrel monotherapy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02983214.

The emergence of drug resistance in cancer poses the greatest hurdle for successful therapeutic results and is associated with most cancer deaths. In triple negative breast cancer (TNBC), due to the lack of specific therapeutic targets, systemic chemotherapy is at the forefront of treatments, but it only benefits a fraction of patients because of the development of resistance. Cancer cells may possess an innate resistance to chemotherapeutic agents or develop new mechanisms of acquired resistance after long-term drug exposure. Such mechanisms involve an interplay between genetic, epigenetic and metabolic alterations that enable cancer cells to evade therapy. In this work, we generated and characterized a chemoresistant TNBC cell line to be used for the investigation of mechanisms that drive resistance to paclitaxel. Transcriptomic analysis highlighted the important role of metabolic-associated pathways in the resistant cells, prompting us to employ ¹H-NMR to explore the metabolome and lipidome of these cells. We identified and described herein numerous metabolites and lipids that were significantly altered in the resistant cells. Integrated analysis of our omics data revealed MSMO1, an intermediate enzyme of cholesterol biosynthesis, as a novel mediator of chemoresistance in TNBC. Overall, our data provide a critical insight into the metabolic adaptations that accompany acquired resistance in TNBC and pinpoint potential new targets.