Nanotechnology is expected to open new avenues to fight and prevent disease using atomic scale tailoring of materials. Among the most promising nanomaterials with antibacterial properties are metallic nanoparticles, which exhibit increased chemical activity due to their large surface to volume ratios and crystallographic surface structure. The study of bactericidal nanomaterials is particularly timely considering the recent increase of new resistant strains of bacteria to the most potent antibiotics. This has promoted research in the well known activity of silver ions and silver-based compounds, including silver nanoparticles. The present work studies the effect of silver nanoparticles in the range of 1-100 nm on Gram-negative bacteria using high angle annular dark field (HAADF) scanning transmission electron microscopy (STEM). Our results indicate that the bactericidal properties of the nanoparticles are size dependent, since the only nanoparticles that present a direct interaction with the bacteria preferentially have a diameter of approximately 1-10 nm.

Expression of the type II voltage-dependent sodium channel gene is restricted to neurons by a silencer element active in nonneuronal cells. We have cloned cDNA coding for a transcription factor (REST) that binds to this silencer element. Expression of a recombinant REST protein confers the ability to silence type II reporter genes in neuronal cell types lacking the native REST protein, whereas expression of a dominant negative form of REST in nonneuronal cells relieves silencing mediated by the native protein. REST transcripts in developing mouse embryos are detected ubiquitously outside of the nervous system. We propose that expression of the type II sodium channel gene in neurons reflects a default pathway that is blocked in nonneuronal cells by the presence of REST.

Triple-negative breast cancer (TNBC) cells are deficient in estrogen, progesterone and ERBB2 receptor expression, presenting a particularly challenging therapeutic target due to their highly invasive nature and relatively low response to therapeutics. There is an absence of specific treatment strategies for this tumor subgroup, and hence TNBC is managed with conventional therapeutics, often leading to systemic relapse. In terms of histology and transcription profile these cancers have similarities to BRCA-1-linked breast cancers, and it is hypothesized that BRCA1 pathway is non-functional in this type of breast cancer. In this review article, we discuss the different receptors expressed by TNBC as well as the diversity of different signaling pathways targeted by TNBC therapeutics, for example, Notch, Hedgehog, Wnt/b-Catenin as well as TGF-beta signaling pathways. Additionally, many epidermal growth factor receptor (EGFR), poly (ADP-ribose) polymerase (PARP) and mammalian target of rapamycin (mTOR) inhibitors effectively inhibit the TNBCs, but they face challenges of either resistance to drugs or relapse. The resistance of TNBC to conventional therapeutic agents has helped in the advancement of advanced TNBC therapeutic approaches including hyperthermia, photodynamic therapy, as well as nanomedicine-based targeted therapeutics of drugs, miRNA, siRNA, and aptamers, which will also be discussed. Artificial intelligence is another tool that is presented to enhance the diagnosis of TNBC.

The type II voltage-dependent sodium channel is present in neuronal cells, where it mediates the propagation of nerve impulses. Restricted expression of the type II sodium channel gene to neurons is due, at least in part, to binding of the repressor protein REST (also termed NRSF or XBR) to the RE1 (also called NRSE) sequence in the type II sodium channel gene. Previous studies have shown that a domain in REST containing eight GL1-Krüppel zinc finger motifs mediates DNA binding. Deletional and GAL4-fusion gene analyses now reveal repressor domains that lie outside of the DNA-binding domain in both the amino and carboxyl termini of REST. Mutational analysis further identifies a single zinc finger motif in the carboxyl-terminal domain as being essential for repressing type II sodium channel reporter genes. These studies reveal two domains in REST that may mediate interactions with other proteins involved in restricting expression of a large set of genes to the vertebrate nervous system.The ability to generate action potentials is often due to the presence of voltage-dependent sodium channels in the plasma membranes of the excitable cells. Sodium channels are encoded by a large multigene family, and members of this family are structurally distinct and expressed in a tissue-specific manner (reviewed in ref. 1). The type II sodium channel gene (2, 3) is expressed to high levels exclusively in neurons in the central nervous system (4, 5). Because of this selective expression pattern, the type II sodium channel has provided an excellent model for studies of the mechanisms regulating neural-specific gene expression.Type II sodium channel reporter genes containing 1050 bp of 5Ј flanking sequence are expressed in neuronal cell lines but not in nonneuronal cells, consistent with expression of the endogenous gene. Deletional analysis has identified a 23-bp element in the type II sodium channel regulatory region, termed repressor element 1 (RE1), that prevents expression of type II reporter genes in nonneuronal cell types (6, 7). Removal of the RE1 results in approximately 80-fold derepression of the type II sodium channel reporter gene specifically in nonneuronal cell types. Repressor elements with sequences and functional properties similar to those of the type II sodium channel RE1 are present in the regulatory region of several other genes expressed exclusively in the nervous system (reviewed in ref. 8), including SCG10 (9, 10), synapsin (11), the ␤1 subunit of the nicotinic acetylcholine receptor (12), the muscarinc M4 receptor (13,14), and neural-glial cell adhesion molecule (15). The widespread occurrence of RE1-like sequences in different genes suggests a more global role of repression in restricting gene expression to the nervous system. Recombinant RE1-silencing transcription factor (REST) is sufficient to repress reporter genes containing RE1-like target sequences in cotransfection analyses of neuronal cells (8,16,17). The deduced primary structure of REST does not reveal any amino acid homologies which wo...

Cannabidiol (CBD) has been used to treat a variety of cancers and inflammatory conditions with controversial results. In previous work, we have shown that breast cancer MCF-7 cells, selected by their response to inflammatory IL-1β cytokine, acquire a malignant phenotype (6D cells) through an epithelial–mesenchymal transition (EMT). We evaluated CBD as a potential inhibitor of this transition and inducer of reversion to a non-invasive phenotype. It decreased 6D cell viability, downregulating expression of receptor CB1. The CBD blocked migration and progression of the IL-1β-induced signaling pathway IL-1β/IL-1RI/β-catenin, the driver of EMT. Cannabidiol reestablished the epithelial organization lost by dispersion of the cells and re-localized E-cadherin and β-catenin at the adherens junctions. It also prevented β-catenin nuclear translocation and decreased over-expression of genes for ∆Np63α, BIRC3, and ID1 proteins, induced by IL-1β for acquisition of malignant features. Cannabidiol inhibited the protein kinase B (AKT) activation, a crucial effector in the IL-1β/IL-1RI/β-catenin pathway, indicating that at this point there is crosstalk between IL-1β and CBD signaling which results in phenotype reversion. Our 6D cell system allowed step-by-step analysis of the phenotype transition and better understanding of mechanisms by which CBD blocks and reverts the effects of inflammatory IL-1β in the EMT.

No abstract

No abstract

A multifunctional magneto-plasmonic CoFe2O4@Au core-shell nanoparticle was developed by iterative-seeding based method. This nanocargo consists of a cobalt ferrite kernel as a core (Nk) and multiple layers of gold as a functionalizable active stratum, (named as Nk@A after fifth iteration). Nk@A helps in augmenting the physiological stability and enhancing surface plasmon resonance (SPR) property. The targeted delivery of Doxorubicin using Nk@A as a nanopayload is demonstrated in this report. The drug release profile followed first order rate kinetics optimally at pH 5.4, which is considered as an endosomal pH of cells. The cellular MR imaging showed that Nk@A is an efficient T2 contrast agent for both L6 (r2-118.08 mM−1s−1) and Hep2 (r2-217.24 mM−1s−1) cells. Microwave based magnetic hyperthermia studies exhibited an augmentation in the temperature due to the transformation of radiation energy into heat at 2.45 GHz. There was an enhancement in cancer cell cytotoxicity when hyperthermia combined with chemotherapy. Hence, this single nanoplatform can deliver 3-pronged theranostic applications viz., targeted drug-delivery, T2 MR imaging and hyperthermia.