Pharmaceuticals2015, 8(4), 836-847; doi:10.3390/ph8040836 - published 25 November 2015 Show/Hide Abstract
Abstract: The interferon (IFN) family of cytokines not only has antiviral properties at various steps in the viral replication cycle, but also anticancer activity through multiple pathways that include inhibiting cell proliferation, regulating cellular responses to inducers of apoptosis and modulating angiogenesis and the immune system. IFNs are known to induce their biological activity through the induction of protein encoding IFN-stimulated genes. However, recent studies have established that IFNs also induce the expression of microRNAs (miRNAs), which are small endogenous non-coding RNAs that suppress gene expression at the post-transcriptional level. MiRNAs play critical roles in tumorigenesis and have been implicated to act as either oncogenes or tumor suppressors in various human cancers. Therefore, IFN-induced miRNAs play an important role, not only in the host response to innate immune response to cancer, but also in the tumorigenic process itself. Furthermore, IFN-induced miRNAs may participate in and/or orchestrate antiviral defense in certain viral infections. In this review, we describe our recent studies on the induction of miR-21 by type I IFN, the role of the STAT3 and NFκB signaling pathways in IFN-induced miR-21 expression, the role of miR-21 in different cancers and the role of miR-21 in regulating the antiviral response.
Pharmaceuticals2015, 8(4), 816-835; doi:10.3390/ph8040816 - published 25 November 2015 Show/Hide Abstract
Abstract: Biofilms are complex communities of microorganisms in organized structures attached to surfaces. Importantly, biofilms are a major cause of bacterial infections in humans, and remain one of the most significant challenges to modern medical practice. Unfortunately, conventional therapies have shown to be inadequate in the treatment of most chronic biofilm infections based on the extraordinary innate tolerance of biofilms to antibiotics. Antagonists of quorum sensing signaling molecules have been used as means to control biofilms. QS and other cell-cell communication molecules are able to revert biofilm tolerance, prevent biofilm formation and disrupt fully developed biofilms, albeit with restricted effectiveness. Recently however, it has been demonstrated that Pseudomonas aeruginosa produces a small messenger molecule cis-2-decenoic acid (cis-DA) that shows significant promise as an effective adjunctive to antimicrobial treatment of biofilms. This molecule is responsible for induction of the native biofilm dispersion response in a range of Gram-negative and Gram-positive bacteria and in yeast, and has been shown to reverse persistence, increase microbial metabolic activity and significantly enhance the cidal effects of conventional antimicrobial agents. In this manuscript, the use of cis-2-decenoic acid as a novel agent for biofilm control is discussed. Stimulating the biofilm dispersion response as a novel antimicrobial strategy holds significant promise for enhanced treatment of infections and in the prevention of biofilm formation.
Pharmaceuticals2015, 8(4), 793-815; doi:10.3390/ph8040793 - published 25 November 2015 Show/Hide Abstract
Abstract: Interferon-γ (IFN-γ) affects immune responses in a complex fashion. Its immunostimulatory actions, such as macrophage activation and induction of T helper 1-type responsiveness, are widely acknowledged, however, as documented by a large body of literature, IFN-γ has also the potential to temper inflammatory processes via other pathways. In autoimmune and autoinflammatory disorders, IFN-γ can either play a disease-enforcing role or act as protective agent, depending on the nature of the disease. In animal models of any particular autoimmune disease, certain changes in the induction procedure can reverse the net outcome of introduction or ablation of IFN-γ. Here, we review the role of endogenous IFN-γ in inflammatory disorders and related murine models, with a focus on systemic juvenile idiopathic arthritis (sJIA) and macrophage activation syndrome (MAS). In particular, we discuss our recent findings in a mouse model of sJIA, in which endogenous IFN-γ acts as a regulatory agent, and compare with results from mouse models of MAS. Also, we elaborate on the complexity in the activity of IFN-γ and the resulting difficulty of predicting its value or that of its antagonists as treatment option.
Pharmaceuticals2015, 8(4), 778-792; doi:10.3390/ph8040778 - published 17 November 2015 Show/Hide Abstract
Abstract: Staphylococcus aureus is a notorious pathogen with a propensity to cause chronic, non-healing wounds. Bacterial persisters have been implicated in the recalcitrance of S. aureus infections, and this motivated us to examine the persistence of S. aureus to ciprofloxacin, a quinolone antibiotic. Upon treatment of exponential phase S. aureus with ciprofloxacin, we observed that survival was a non-monotonic function of ciprofloxacin concentration. Maximal killing occurred at 1 µg/mL ciprofloxacin, which corresponded to survival that was up to ~40-fold lower than that obtained with concentrations ≥ 5 µg/mL. Investigation of this phenomenon revealed that the non-monotonic response was associated with prophage induction, which facilitated killing of S. aureus persisters. Elimination of prophage induction with tetracycline was found to prevent cell lysis and persister killing. We anticipate that these findings may be useful for the design of quinolone treatments.
Pharmaceuticals2015, 8(4), 758-777; doi:10.3390/ph8040758 - published 17 November 2015 Show/Hide Abstract
Abstract: The “Journées Franco-Belges de Pharmacochimie” is a recognized two-day annual meeting on Medicinal Chemistry that is renowned for the advanced science presented, conviviality, and outstanding opportunities for senior and young scientists to exchange knowledge. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.
Pharmaceuticals2015, 8(4), 711-757; doi:10.3390/ph8040711 - published 16 November 2015 Show/Hide Abstract
Abstract: Plant antimicrobial peptides (AMPs) have evolved differently from AMPs from other life forms. They are generally rich in cysteine residues which form multiple disulfides. In turn, the disulfides cross-braced plant AMPs as cystine-rich peptides to confer them with extraordinary high chemical, thermal and proteolytic stability. The cystine-rich or commonly known as cysteine-rich peptides (CRPs) of plant AMPs are classified into families based on their sequence similarity, cysteine motifs that determine their distinctive disulfide bond patterns and tertiary structure fold. Cystine-rich plant AMP families include thionins, defensins, hevein-like peptides, knottin-type peptides (linear and cyclic), lipid transfer proteins, α-hairpinin and snakins family. In addition, there are AMPs which are rich in other amino acids. The ability of plant AMPs to organize into specific families with conserved structural folds that enable sequence variation of non-Cys residues encased in the same scaffold within a particular family to play multiple functions. Furthermore, the ability of plant AMPs to tolerate hypervariable sequences using a conserved scaffold provides diversity to recognize different targets by varying the sequence of the non-cysteine residues. These properties bode well for developing plant AMPs as potential therapeutics and for protection of crops through transgenic methods. This review provides an overview of the major families of plant AMPs, including their structures, functions, and putative mechanisms.