A novel cationic ß-cyclodextrin decorated with a choline-like pendant exhibits Iodophor, Mucoadhesive and bactericidal properties.

Iodine is a vital microelement and a powerful antiseptic with a rapid and broad spectrum of action. The development of iodophor compounds to improve the solubility and stability of iodine is still challenging. Here, we report the synthesis of a novel cationic ß-cyclodextrin bearing a choline-like pendant (ß-CD-Chol) designed to complex and deliver iodine to bacterial cells. The characterization of ß-CD-Chol and the investigation of the inclusion complex with iodine were performed by NMR spectroscopy, mass spectrometry, UV-vis spectrophotometry, isothermal titration calorimetry, and dynamic light scattering. The functionalization with the positively charged unit conferred improved water-solubility, mucoadhesivity, and iodine complexation efficiency to the ß-CD scaffold. The water-soluble ß-CD-Chol/iodine complex efficiently formed both in solution and by solid-vapor reaction. The solid complex exhibited a significant stability for months. Iodine release from the inclusion complex was satisfactory and the bactericidal activity was proved against a Staphylococcus epidermidis strain. The absence of cytotoxicity tested on human keratinocytes and the improved mucoadhesivity make ß-CD-Chol a promising drug delivery system and an appealing iodophor candidate for iodine-based antisepsis including mucosa disinfection.

p-Sulfonato-Calix[4]arene Micelles Stabilize a Povidone Iodine Solution: Supramolecular Interactions, Iodine Retention, and Bactericidal Activity.

Povidone iodine (PVPI) is an antiseptic widely used against a broad spectrum of pathogens. However, undesired side-effects are still associated with PVPI treatment due to the irritant effect of iodine. Reducing the concentration of a PVPI formulation could provide safer and more friendly formulations, for routine use and applications in very delicate organs such as the eye. However, managing the storage of a low-concentration solution of PVPI is challenging due to the high iodine volatility. In this study, we demonstrated that an amphiphilic p-sulfonato-calix[4]arene derivative forming micelles (SC4OC6) improves the stability of a 0.1% PVPI aqueous buffered solution. UV-vis and NMR spectra as well as dynamic and electrophoretic light scattering measurements showed that SC4OC6 establishes non-covalent supramolecular interactions with PVPI, resulting in the formation of nanoaggregates with a negatively charged surface. Isothermal titration calorimetry provided the aggregation parameters and evidenced that the formation of the supramolecular assembly is an enthalpically favored process. The interaction of SC4OC6 with PVPI enhances the iodine retention and stability of the solution without affecting the rapid and effective bactericidal activity of PVPI, as demonstrated by a time-killing assay with Staphylococcus epidermidis.

Haloperidol Metabolite II Valproate Ester (S)-(-)-MRJF22: Preliminary Studies as a Potential Multifunctional Agent Against Uveal Melanoma.

Increased angiogenesis and vascular endothelial growth factor (VEGF) levels contribute to higher metastasis and mortality in uveal melanoma (UM), an aggressive malignancy of the eye in adults. (±)-MRJF22, a prodrug of the sigma (σ) ligand haloperidol metabolite II conjugated with the histone deacetylase (HDAC) inhibitor valproic acid, has previously demonstrated a promising antiangiogenic activity. Herein, the asymmetric synthesis of (R)-(+)-MRJF22 and (S)-(-)-MRJF22 was performed to investigate their contribution to (±)-MRJF22 antiangiogenic effects in human retinal endothelial cells (HREC) and to assess their therapeutic potential in primary human uveal melanoma (UM) 92-1 cell line. While both enantiomers displayed almost identical capabilities to reduce cell viability than the racemic mixture, (S)-(-)-MRJF22 exhibited the highest antimigratory effects in endothelial and tumor cells. Given the fundamental contribution of cell motility to cancer progression, (S)-(-)-MRJF22 may represent a promising candidate for novel antimetastatic therapy in patients with UM.

Secondary metabolic profiles and anticancer actions from fruit extracts of immature pomegranates.

Immature fruits from Punica granatum L. thinning are a neglected side product of pomegranate production with cumbersome disposal costs for farmers. To explore value potential of immature fruits from pomegranate 'Wonderful' cultivars, the compositional landscapes and antitumorigenic activities of pomegranate extracts from two different stages of maturation were assessed. Cancer cell proliferation and cytotoxicity was quantified in human lung H1299 and colon HCT116 adenocarcinomas by crystal violet staining, MTS assay and caspase-3 activity. High performance liquid chromatography-diode array detector (HPLC/DAD) and high performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC/ESI-MS) analyses indicate that immature fruits are rich sources of gallotannins and ellagitannins, with the highest amounts contained in immature fruit peels. Biological investigations reveal a robust anticancer activity by those immature P. granatum fruit extracts, which reflected induction of tumor cytotoxicity and cell death mechanisms. Together, present observations suggest P. granatum byproducts from the thinning process may provide unexplored values for virtuous circular economy.

Deletions of Chromosome 7q Affect Nuclear Organization and HLXB9Gene Expression in Hematological Disorders.

The radial spatial positioning of individual gene loci within interphase nuclei has been associated with up- and downregulation of their expression. In cancer, the genome organization may become disturbed due to chromosomal abnormalities, such as translocations or deletions, resulting in the repositioning of genes and alteration of gene expression with oncogenic consequences. In this study, we analyzed the nuclear repositioning of HLXB9 (also called MNX1), mapping at 7q36.3, in patients with hematological disorders carrying interstitial deletions of 7q of various extents, with a distal breakpoint in 7q36. We observed that HLXB9 remains at the nuclear periphery, or is repositioned towards the nuclear interior, depending upon the compositional properties of the chromosomal regions involved in the rearrangement. For instance, a proximal breakpoint leading the guanine-cytosine (GC)-poor band 7q21 near 7q36 would bring HLXB9 to the nuclear periphery, whereas breakpoints that join the GC-rich band 7q22 to 7q36 would bring HLXB9 to the nuclear interior. This nuclear repositioning is associated with transcriptional changes, with HLXB9 in the nuclear interior becoming upregulated. Here we report an in cis rearrangement, involving one single chromosome altering gene behavior. Furthermore, we propose a mechanistic model for chromatin reorganization that affects gene expression via the influences of new chromatin neighborhoods.

HLXB9 gene expression, and nuclear location during in vitro neuronal differentiation in the SK-N-BE neuroblastoma cell line.

Different parts of the genome occupy specific compartments of the cell nucleus based on the gene content and the transcriptional activity. An example of this is the altered nuclear positioning of the HLXB9 gene in leukaemia cells observed in association with its over-expression. This phenomenon was attributed to the presence of a chromosomal translocation with breakpoint proximal to the HLXB9 gene. Before becoming an interesting gene in cancer biology, HLXB9 was studied as a developmental gene. This homeobox gene is also known as MNX1 (motor neuron and pancreas homeobox 1) and it is relevant for both motor neuronal and pancreatic beta cells development. A spectrum of mutations in this gene are causative of sacral agenesis and more broadly, of what is known as the Currarino Syndrome, a constitutional autosomal dominant disorder. Experimental work on animal models has shown that HLXB9 has an essential role in motor neuronal differentiation. Here we present data to show that, upon treatment with retinoic acid, the HLXB9 gene becomes over-expressed during the early stages of neuronal differentiation and that this corresponds to a reposition of the gene in the nucleus. More precisely, we used the SK-N-BE human neuroblastoma cell line as an in vitro model and we demonstrated a transient transcription of HLXB9 at the 4th and 5th days of differentiation that corresponded to the presence, predominantly in the cell nuclei, of the encoded protein HB9. The nuclear positioning of the HLXB9 gene was monitored at different stages: a peripheral location was noted in the proliferating cells whereas a more internal position was noted during differentiation, that is while HLXB9 was transcriptionally active. Our findings suggest that HLXB9 can be considered a marker of early neuronal differentiation, possibly involving chromatin remodeling pathways.