Cancer development is highly associated to the physiological state of the tumor microenvironment (TME). Despite the existing heterogeneity of tumors from the same or from different anatomical locations, common features can be found in the TME maturation of epithelial-derived tumors. Genetic alterations in tumor cells result in hyperplasia, uncontrolled growth, resistance to apoptosis, and metabolic shift towards anaerobic glycolysis (Warburg effect). These events create hypoxia, oxidative stress and acidosis within the TME triggering an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e.g., fibroblasts) and immune cells (lymphocytes and macrophages), inducing angiogenesis and, ultimately, resulting in metastasis. Exosomes secreted by TME cells are central players in all these events. The TME profile is preponderant on prognosis and impacts efficacy of anti-cancer therapies. Hence, a big effort has been made to develop new therapeutic strategies towards a more efficient targeting of TME. These efforts focus on: (i) therapeutic strategies targeting TME components, extending from conventional therapeutics, to combined therapies and nanomedicines; and (ii) the development of models that accurately resemble the TME for bench investigations, including tumor-tissue explants, “tumor on a chip” or multicellular tumor-spheroids.

We present the YEAst Search for Transcriptional Regulators And Consensus Tracking (YEASTRACT; ) database, a tool for the analysis of transcription regulatory associations in Saccharomyces cerevisiae. This database is a repository of 12 346 regulatory associations between transcription factors and target genes, based on experimental evidence which was spread throughout 861 bibliographic references. It also includes 257 specific DNA-binding sites for more than a hundred characterized transcription factors. Further information about each yeast gene included in the database was obtained from Saccharomyces Genome Database (SGD), Regulatory Sequences Analysis Tools and Gene Ontology (GO) Consortium. Computational tools are also provided to facilitate the exploitation of the gathered data when solving a number of biological questions as exemplified in the Tutorial also available on the system. YEASTRACT allows the identification of documented or potential transcription regulators of a given gene and of documented or potential regulons for each transcription factor. It also renders possible the comparison between DNA motifs, such as those found to be over-represented in the promoter regions of co-regulated genes, and the transcription factor-binding sites described in the literature. The system also provides an useful mechanism for grouping a list of genes (for instance a set of genes with similar expression profiles as revealed by microarray analysis) based on their regulatory associations with known transcription factors.

Infectious diseases remain one of the leading causes of morbidity and mortality worldwide. The WHO and CDC have expressed serious concern regarding the continued increase in the development of multidrug resistance among bacteria. Therefore, the antibiotic resistance crisis is one of the most pressing issues in global public health. Associated with the rise in antibiotic resistance is the lack of new antimicrobials. This has triggered initiatives worldwide to develop novel and more effective antimicrobial compounds as well as to develop novel delivery and targeting strategies. Bacteria have developed many ways by which they become resistant to antimicrobials. Among those are enzyme inactivation, decreased cell permeability, target protection, target overproduction, altered target site/enzyme, increased efflux due to over-expression of efflux pumps, among others. Other more complex phenotypes, such as biofilm formation and quorum sensing do not appear as a result of the exposure of bacteria to antibiotics although, it is known that biofilm formation can be induced by antibiotics. These phenotypes are related to tolerance to antibiotics in bacteria. Different strategies, such as the use of nanostructured materials, are being developed to overcome these and other types of resistance. Nanostructured materials can be used to convey antimicrobials, to assist in the delivery of novel drugs or ultimately, possess antimicrobial activity by themselves. Additionally, nanoparticles (e.g., metallic, organic, carbon nanotubes, etc.) may circumvent drug resistance mechanisms in bacteria and, associated with their antimicrobial potential, inhibit biofilm formation or other important processes. Other strategies, including the combined use of plant-based antimicrobials and nanoparticles to overcome toxicity issues, are also being investigated. Coupling nanoparticles and natural-based antimicrobials (or other repurposed compounds) to inhibit the activity of bacterial efflux pumps; formation of biofilms; interference of quorum sensing; and possibly plasmid curing, are just some of the strategies to combat multidrug resistant bacteria. However, the use of nanoparticles still presents a challenge to therapy and much more research is needed in order to overcome this. In this review, we will summarize the current research on nanoparticles and other nanomaterials and how these are or can be applied in the future to fight multidrug resistant bacteria.

Abstract:The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. Apart from the already marketed drugs, there are many other being investigated for their promising activity against several malignancies. In particular, anticancer research has been capitalizing on the intrinsic versatility and dynamic core scaffold of these compounds. Nevertheless, as for any other promising anticancer drugs, heterocyclic compounds do not come without shortcomings. In this review, we provide for a concise overview of heterocyclic active compounds and families and their main applications in medicine. We shall focus on those suitable for cancer therapy while simultaneously addressing main biochemical modes of action, biological targets, structure-activity relationships as well as intrinsic limitation issues in the use of these compounds. Finally, considering the advent of nanotechnology for effective selective targeting of drugs, we shall discuss fundamental aspects and considerations on nanovectorization of such compounds that may improve pharmacokinetic/pharmacodynamic properties of heterocycles.