Synthesis and anticancer activity of Pt(0)-olefin complexes bearing 1,3,5-triaza-7-phosphaadamantane and N-heterocyclic carbene ligands

A series of Pt(0)-η2-olefin complexes bearing 1,3,5-triaza-7-phosphaadamantane (PTA) or N-heterocyclic carbenes are prepared following different synthetic strategies depending on the nature of coordinated alkene and spectator ligands. These new platinum(0) derivatives have been tested in vitro as anticancer agents toward three different tumor (human ovarian cancer A2780 and A2780cis and K562 myelogenous leukemia) and one non-tumor (Hacat keratinocytes) cell lines, proving to be in several cases highly and selectively cytotoxic against ovarian cancer cells. Furthermore, this antiproliferative effect is associated with the activation of an apoptosis process. In particular, complexes equipped with PTA as spectator ligand give comparable IC50 values on A2780 (cisplatin sensitive) and A2780cis (cisplatin resistant) cell lines, indirectly proving that these new Pt(0) substrates act with a mechanism of action conceivably different from cisplatin. This hypothesis is also confirmed by the fact that our compounds, in contrast to cisplatin, are not able to promote erythroid-differentiation activity on the K562 myelogenous leukemia cell line

Efficient Delivery of MicroRNA and AntimiRNA Molecules Using an Argininocalix[4]arene Macrocycle

MicroRNAs (miRNAs) are short non-coding RNA molecules acting as gene regulators by repressing translation or by inducing degradation of the target RNA transcripts. Altered expression of miRNAs may be involved in the pathogenesis of many severe human diseases, opening new avenues in the field of therapeutic strategies, i.e., miRNA targeting or miRNA mimicking. In this context, the efficient and non-toxic delivery of premiRNA and antimiRNA molecules might be of great interest. The aim of the present paper is to determine whether an argininocalix[4]arene is able to efficiently deliver miRNA, premiRNA, and antimiRNA molecules to target cells, preserving their biological activity. This study points out that (1) the toxicity of argininocalix[4]arene 1 is low, and it can be proposed for long-term treatment of target cells, being that this feature is a pre-requisite for the development of therapeutic protocols; (2) the delivery of premiRNA and antimiRNA molecules is efficient, being higher when compared with reference gold standards available; and (3) the biological activity of the premiRNAs and antimiRNAs is maintained. This was demonstrated using the argininocalix[4]arene 1 in miRNA therapeutic approaches performed on three well-described experimental model systems: (1) the induction of apoptosis by antimiR-221 in glioma U251 cells; (2) the induction of apoptosis by premiR-124 in U251 cells; and (3) the inhibition of pro-inflammatory IL-8 and IL-6 genes in cystic fibrosis IB3-1 cells. Our results demonstrate that the argininocalix[4]arene 1 should be considered a very useful delivery system for efficient transfer to target cells of both premiRNA and antimiRNA molecules, preserving their biological activity

Increased frequency of activated CD8+ T cell effectors in patients with psoriatic arthritis

The aim of this study is to identify subsets of T cells differentially represented in the circulation of patients with psoriatic arthritis and to evaluate the possibility that they can recirculate between peripheral blood and the inflamed joints. We analyzed the phenotype and cytokine expression in circulating CD8+ and CD4+ T cells in 69 subjects: 28 with cutaneous psoriasis, 15 patients with psoriatic arthritis, and 26 healthy subjects. In the circulation, the percentage of each subset was compared among the groups and correlation was calculated with the serum concentration of C-reactive protein. To investigate the migration of T cells towards the inflamed joints, we performed a transwell migration assay towards patient serum and synovial fluid. In selected patients we analyzed in parallel T cells from peripheral blood and from synovial fluid. In the circulation, we found increased percentage of CD8+ CCR6+ T cell effectors expressing CD69 and of IL-17-producing T cells in patients with psoriatic arthritis. CD8+ effector/effector memory T cells showed increased migration towards synovial fluid. Finally, in synovial fluid we found accumulation of CXCR3+ CD8+ T cells and CD69+ cells. CD4+ T cells in the two compartments shared many similarities with CD8+ T cells. The results indicate a role for memory T cell effectors in systemic and joint manifestations of psoriatic arthritis

Nucleosynthesis Calculations for the Ejecta of Neutron Star Coalescences

We present the results of fully dynamical r-process network calculations for the ejecta of neutron star mergers (NSMs). The late stages of the inspiral and the final violent coalescence of a neutron star binary have been calculated in detail using a 3D hydrodynamics code (Newtonian gravity plus backreaction forces emerging from the emission of gravitational waves) and a realistic nuclear equation of state. The found trajectories for the ejecta serve as input for dynamical r-process calculations where all relevant nuclear reactions (including beta-decays depositing nuclear energy in the expanding material) are followed. We find that all the ejected material undergoes r-process. For an initial Ye close to 0.1 the abundance distributions reproduce very accurately the solar r-process pattern for nuclei with A above 130. For lighter nuclei strongly underabundant (as compared to solar) distributions are encountered. We show that this behaviour is consistent with the latest observations of very old, metal-poor stars, despite simplistic arguments that have recently been raised against the possibility of NSM as possible sources of Galactic r-process material.Comment: 5 pages, 2 figures, proceedings of Nuclei in the Cosmos 2000, to be published in Nucl. Phys. A; minor correctio

Phosphorus cycling and burial in sediments of a seasonally hypoxic marine basin

Recycling of phosphorus (P) from sediments contributes to the development of bottom-water hypoxia in many coastal systems. Here, we present results of a year-long assessment of P dynamics in sediments of a seasonally hypoxic coastal marine basin (Lake Grevelingen, the Netherlands) in 2012. Sequential phosphorus extractions (SEDEX) and X-ray absorption spectroscopy (XAS) indicate that P was adsorbed to Fe-(III)-(oxyhydr)oxides when cable bacteria were active in the surface sediments in spring. With the onset of summer hypoxia, sulphide-induced dissolution of the Fe-(III)-(oxyhydr)oxides led to P release to the pore water and overlying water. The similarity in authigenic Ca-P concentrations in the sediment and suspended matter suggest that Ca-P is not formed in situ. The P burial efficiency was ≤ 32%. Hypoxia-driven sedimentary P recycling had a major impact on the water-column chemistry in the basin in 2012. Water-column monitoring data indicate up to ninefold higher surface water concentrations of phosphate in the basin in the late 1970s and a stronger hypoxia-driven seasonal P release from the sediment. The amplified release of P from the sediment in the past is attributed to the presence of a larger pool of Fe-bound P in the basin prior to the first onset of hypoxia. Given that P is not limiting, primary production in the basin has not been affected by the decadal changes in P availability and recycling over the past 40 years. The changes in P dynamics on decadal time scales wer

Pharmacological Modulators of Sphingolipid Metabolism for the Treatment of Cystic Fibrosis Lung Inflammation

Cystic Fibrosis (CF) lung disease is characterised by progressive chronic infection and inflammation of the airways. This prolonged airway inflammatory response leads to irreversible lung damage and fibrosis which is believed to be driven by two distinct, coordinated events: a) a defective cystic fibrosis transmembrane regulator (CFTR) causes airway surface dehydration and increased mucus viscosity leading to chronic colonization with Pseudomonas aeruginosa (P.aeruginosa) (Boucher, 2007); b) mutated CFTR triggers the generation of pro-inflammatory and chemotactic cytokines orchestrated by bronchial epithelial cells, independently of infection (Rubin, 2007; Elizur et al., 2008). The chemokine IL-8, abundantly expressed at sites of chronic inflammation, seems to play a major role in driving the formation of neutrophil (PMN)-rich exudates into the lung of CF patients (Khan et al., 1995; Noah et al., 1997; DiMango et al., 1998; Puchelle et al., 2001; Joseph et al., 2005; Perez et al., 2007). Therefore, reduction of the exaggerated production of IL-8 is key therapeutic target in CF. Anti-inflammatory drugs are an attractive therapeutic tool in CF aimed to decrease the rate of decline in lung function. However, the inherent complexity of the inflammatory response combined with the obvious dependency on this response to contain infection and the side effect profiles of common anti-inflammatories, have made identifying the most suitable therapy a major priority. Consensus is growing on sphingolipids (SLs) as novel targets to cure pulmonary disorders including CF, since modulation of cellular ceramide reduces lung inflammation (Lahiri and Futerman, 2007; Uhlig and Gulbins, 2008). The results in the area of ceramide and CF pathophysiology are very interesting, although contradicting due to the animal models used and methods of ceramide detection (Wojewodka , 2011). The accumulation of ceramide has been identified as one of the key regulators of inflammation in CF airways in different CFTR-/- mouse models (Teichgraber, 2008). On the contrary, decreased ceramide levels have been shown in CFTR ko mice (Guibault, 2008). The possible explanation for this discrepancy seems to be the special diet required for CFTR ko mice, that severely affects the concentration of SLs. Other possible causes, such as genetic determinants, could influence individual levels of SLs (Hicks, 2009). In a different study, no significant difference has been found in basal ceramide levels in immortalised CF bronchial epithelial cells and lung homogenate from CFTR ko mice compared to wild type cells and mice (Yu, 2009). Very importantly, ceramide has been demonstrated to accumulate in the lower airways of CF patients and to be positively associated with neutrophilic inflammation (Brodlie, 2010), supporting the hypothesis that reduction of ceramide may be a therapeutic target for CF lung inflammation. Extending our previous study (Dechecchi, 2008), we have recently demonstrated that the iminosugar N-butyldeoxynojirimycin (miglustat), an inhibitor of the first step in glycosphingolipid (GSL) biosynthesis, reducing the P.aeruginosa induced immunoreactive ceramide expression, produces an anti-inflammatory effect in human bronchial epithelial cells in vitro and down-regulates the neutrophil chemotaxis in murine lungs in vivo (Dechecchi, 2011). These findings strengthen the notion that the metabolism of SLs can be manipulated as a therapeutic option for CF lung disease. With regard to new treatments for CF lung pathology, miglustat deserves great attention since it restores CFTR function in respiratory and pancreatic cells in vitro (Norez, 2006; Dechecchi, 2008) and in CF mice (Lubamba, 2009) and produces an anti-inflammatory effect in vitro and in vivo Dechecchi, 2011). Notably, miglustat is a FDA-approved and EMA−designated orally bioavailable orphan drug, used in Europe and USA for the treatment of Gaucher disease and other GSL storage diseases. In this chapter we review the pre-clinical evidence on the anti-inflammatory effect of miglustat in comparative effectiveness studies with the SL inhibitor amitriptyline and the glucocorticoid (GC) dexamethasone. Importance will be placed on the efficacy of each anti-inflammatory molecule to balance between the anti-inflammatory activity and possible impairment of the host defence

A case of coexisting Warthin tumor and langerhans cell histiocytosis associated with necrosis, eosinophilic abscesses and a granulomatous reaction in intraparotid lymph nodes

We present a patient (50-year-old male) with coexisting Warthin tumor and involvement of two intraparotid lymph nodes by Langerhans cell histiocytosis associated with necrosis, eosinophilic abscesses and a granulomatous reaction. This is the second documented case of this unusual combination of histological changes in nodal Langerhans cell histiocytosis and the first case involving intraparotid lymph nodes occurring together with an ipsilateral Warthin tumor

Nigeria’s Relations with Her Neighbors and the Fight against Terrorism: An Analysis of the Multinational Joint Task Force

This chapter examines Nigeria’s relationship with her immediate neighboring countries in the fight against terrorism. It probed the challenges of national security following the internationalization of Boko Haram terrorist threats, particularly around the Lake Chad basin, and the responses of countries such as Cameroon, Chad, and Niger. These countries, like Nigeria, share borders around the Lake Chad and are the core contributors to the Multinational Joint Task Force (MNJTF). Nigeria is an English-speaking country (former British colony), while these other neighbors are historically French colonial territories. Hence, their political, cultural, military, and economic affinities are with France. The varying backgrounds have accounted for the challenges in the subregion including the Boko Haram insurgency and the efforts at military cooperation in tackling it. Consequently, these questions are examined: what factors led to the formation of MNJTF and what role has it played in the counterterrorism strategies of the country? In what ways has the nature of Nigeria’s relations with these countries impacted on the operation of the body? What are the roles of external powers such as France with her domineering influence on these countries in the war against terrorism and how has it promoted Nigeria’s national security interest? The chapter relies on documented materials to interrogate the questions and proffer necessary policy recommendations premised on the findings

Induction of endogenous γ-globin gene expression with decoy oligonucleotide targeting Oct-1 transcription factor consensus sequence

Human β-globin disorders are relatively common genetic diseases cause by mutations in the β-globin gene. Increasing the expression of the γ-globin gene has great benefits in reducing complications associated with these diseases. The Oct-1 transcription factor is involved in the transcriptional regulation of the γ-globin gene. The human γ-globin genes (both Aγ and Gγ-globin genes) carry three Oct-1 transcription factor consensus sequences within their promoter regions. We have studied the possibility of inducing γ-globin gene expression using decoy oligonucleotides that target the Oct-1 transcription factor consensus sequence. A double-stranded 22 bp decoy oligonucleotide containing the Oct-1 consensus sequence was synthesized. The results obtained from our in vitro binding assay revealed a strong competitive binding of the decoy oligonucleotide for the Oct-1 transcription factor. When K562 human erythroleukemia cells were treated with the Oct-1 decoy oligonucleotide, significant increases in the level of the γ-globin mRNA were observed. The results of our western blots further demonstrated significant increases of the fetal hemoglobin (HbF, α2γ2) in the Oct-1 decoy oligonucleotide-treated K562 cells. The results of our immunoprecipitation (IP) studies revealed that the treatment of K562 cells with the Oct-1 decoy oligonucleotide significantly reduced the level of the endogenous γ-globin gene promoter region DNA co-precipitated with the Oct-1 transcription factor. These results suggest that the decoy oligonucleotide designed for the Oct-1 transcription factor consensus sequence could induce expression of the endogenous γ-globin gene through competitive binding of the Oct-1 transcription factor, resulting in activation of the γ-globin genes. Therefore, disrupting the bindings of the Oct-1 transcriptional factors with the decoy oligonucleotide provides a novel approach for inducing expression of the γ-globin genes. It also provides an innovative strategy for the treatment of many disease conditions, including sickle cell anemia and β-thalassemia

Induction of apoptosis of human primary osteoclasts treated with extracts from the medicinal plant Emblica officinalis

<p>Abstract</p> <p>Background</p> <p>Osteoclasts (OCs) are involved in rheumatoid arthritis and in several pathologies associated with bone loss. Recent results support the concept that some medicinal plants and derived natural products are of great interest for developing therapeutic strategies against bone disorders, including rheumatoid arthritis and osteoporosis. In this study we determined whether extracts of <it>Emblica officinalis </it>fruits display activity of possible interest for the treatment of rheumatoid arthritis and osteoporosis by activating programmed cell death of human primary osteoclasts.</p> <p>Methods</p> <p>The effects of extracts from <it>Emblica officinalis </it>on differentiation and survival of human primary OCs cultures obtained from peripheral blood were determined by tartrate-acid resistant acid phosphatase (TRAP)-positivity and colorimetric MTT assay. The effects of <it>Emblica officinalis </it>extracts on induction of OCs apoptosis were studied using TUNEL and immunocytochemical analysis of FAS receptor expression. Finally, <it>in vitro </it>effects of <it>Emblica officinalis </it>extracts on NF-kB transcription factor activity were determined by gel shift experiments.</p> <p>Results</p> <p>Extracts of <it>Emblica officinalis </it>were able to induce programmed cell death of mature OCs, without altering, at the concentrations employed in our study, the process of osteoclastogenesis. <it>Emblica officinalis </it>increased the expression levels of Fas, a critical member of the apoptotic pathway. Gel shift experiments demonstrated that <it>Emblica officinalis </it>extracts act by interfering with NF-kB activity, a transcription factor involved in osteoclast biology. The data obtained demonstrate that <it>Emblica officinalis </it>extracts selectively compete with the binding of transcription factor NF-kB to its specific target DNA sequences. This effect might explain the observed effects of <it>Emblica officinalis </it>on the expression levels of interleukin-6, a NF-kB specific target gene.</p> <p>Conclusion</p> <p>Induction of apoptosis of osteoclasts could be an important strategy both in interfering with rheumatoid arthritis complications of the bone skeleton leading to joint destruction, and preventing and reducing osteoporosis. Accordingly, we suggest the application of <it>Emblica officinalis </it>extracts as an alternative tool for therapy applied to bone diseases.</p