In vitro activities of novel 4-HPR derivatives on a panel of rhabdoid and other tumor cell lines

<p>Abstract</p> <p>Background</p> <p>Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis. N-(4-hydroxy phenyl) retinamide (4-HPR or fenretinide) is a potential chemotherapeutic for RTs with activity correlated to its ability to down-modulate Cyclin D1. Previously, we synthesized novel halogen-substituted and peptidomimetic-derivatives of 4-HPR that retained activity in MON RT cells. Here we analyzed the effect of 4-HPR in inhibiting the growth of several RT, glioma, and breast cancer cell lines and tested their effect on cell cycle, apoptosis and Cyclin D1 expression.</p> <p>Methods</p> <p>Effect of compounds on RT cell cycle profiles, and cell death were assessed by MTS cell survival assays and FACS analysis. The effects of treatment on Cyclin D1 expression were determined by immunoblotting. The efficacy of these compounds on glioma and breast cancer cell lines was also determined using MTS assays.</p> <p>Results</p> <p>Low micromolar concentrations of 4-HPR derivatives inhibited cell survival of all RT cells tested. The 4-HPR derivatives altered RT cell cycle profiles and induced high levels of cell death that was correlated with their potency. ATRA exhibited high IC₅₀values in all cell lines tested and did not cause cell death. In MON RT cells, the iodo-substituted compounds were more active than 4-HPR in inducing cell cycle arrest and apoptosis. Additionally, the activity of the compounds correlated with their ability to down-modulate Cyclin D1: while active compounds reduced Cyclin D1 levels, inactive ATRA did not. In glioma and breast cancer cell lines, 4-HPR and 4-HPR derivatives showed variable efficacy.</p> <p>Conclusions</p> <p>Here we demonstrate, for the first time, that the inhibitory activities of novel halogen-substituted and peptidomimetic derivatives of 4-HPR are correlated to their ability to induce cell death and down-modulate Cyclin D1. These 4-HPR derivatives showed varied potencies in breast cancer and glioma cell lines. These data indicate that further studies are warranted on these derivatives of 4-HPR due to their low IC₅₀s in RT cells. These derivatives are of general interest, as conjugation of halogen radioisotopes such as ¹⁸F, ¹²⁴I, or ¹³¹I to 4-HPR will allow us to combine chemotherapy and radiotherapy with a single drug, and to perform PET/SPECT imaging studies in the future.</p

Formulation and evaluation of gliclazide loaded controlled release microspheres

The aim of this study was to formulate gliclazide loaded controlled release microspheres. Microspheres were prepared by quasi emulsion solvent diffusion technique using eudragit RLPO, eudragit RSPO and with their various combinations. The effect of different formulation variables (drug-polymer ratio and polymer-polymer ratio) on percent yield, mean particle size, encapsulation efficiency and in vitro release of drug were evaluated. In vivo test of the optimized formulation was performed on streptozotocin induced type-2 diabetic rat model. The formulated microspheres showed higher encapsulation efficiencies within the range of 72-84 %. Mean particle size, encapsulation efficiency and in vitro release were found to be affected by changing in formulation variables. In vitro release study revealed the gliclazide release from the microspheres was extended for more than 12 h. In vivo hypoglycemic effect of microspheres was more than 25 h suggesting microspheres are a valuable system for sustained delivery of gliclazide.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Formulation and evaluation of gliclazide loaded controlled release microspheres

The aim of this study was to formulate gliclazide loaded controlled release microspheres. Microspheres were prepared by quasi emulsion solvent diffusion technique using eudragit RLPO, eudragit RSPO and with their various combinations. The effect of different formulation variables (drug-polymer ratio and polymer-polymer ratio) on percent yield, mean particle size, encapsulation efficiency and in vitro release of drug were evaluated. In vivo test of the optimized formulation was performed on streptozotocin induced type-2 diabetic rat model. The formulated microspheres showed higher encapsulation efficiencies within the range of 72-84 %. Mean particle size, encapsulation efficiency and in vitro release were found to be affected by changing in formulation variables. In vitro release study revealed the gliclazide release from the microspheres was extended for more than 12 h. In vivo hypoglycemic effect of microspheres was more than 25 h suggesting microspheres are a valuable system for sustained delivery of gliclazide.Colegio de Farmacéuticos de la Provincia de Buenos Aire

High-coercivity magnetism in nanostructures with strong easy-plane anisotropy

We report the fabrication of a rare-earth-free permanent-magnet material Co3Si in the form of nanoparticles and investigate its magnetic properties by experiments and density-functional theory (DFT). The DFT calculations show that bulk Co3Si has an easy-plane anisotropy with a high K1≈64 Merg/cm3 (6.4 MJ/m3) and magnetic polarization of 9.2 kG (0.92 T). In spite of having a negative anisotropy that generally leads to negligibly low coercivities in bulk crystals, Co3Si nanoparticles exhibit high coercivities (17.4 kOe at 10K and 4.3 kOe at 300 K). This result is a consequence of the unique nanostructure made possible by an effective easy-axis alignment in the cluster-deposition method and explained using micromagnetic analysis as a nanoscale phenomenon involving quantum-mechanical exchange interactions

Formulation and evaluation of gliclazide loaded controlled release microspheres

The aim of this study was to formulate gliclazide loaded controlled release microspheres. Microspheres were prepared by quasi emulsion solvent diffusion technique using eudragit RLPO, eudragit RSPO and with their various combinations. The effect of different formulation variables (drug-polymer ratio and polymer-polymer ratio) on percent yield, mean particle size, encapsulation efficiency and in vitro release of drug were evaluated. In vivo test of the optimized formulation was performed on streptozotocin induced type-2 diabetic rat model. The formulated microspheres showed higher encapsulation efficiencies within the range of 72-84 %. Mean particle size, encapsulation efficiency and in vitro release were found to be affected by changing in formulation variables. In vitro release study revealed the gliclazide release from the microspheres was extended for more than 12 h. In vivo hypoglycemic effect of microspheres was more than 25 h suggesting microspheres are a valuable system for sustained delivery of gliclazide.Colegio de Farmacéuticos de la Provincia de Buenos Aire

The ceramide synthase 2b gene mediates genomic sensing and regulation of sphingosine levels during zebrafish embryogenesis

Sphingosine-1-phosphate (S1P) is generated through phosphorylation of sphingosine by sphingosine kinases (Sphk1 and Sphk2). We show that sphk2 maternal-zygotic mutant zebrafish embryos (sphk2MZ) display early developmental phenotypes, including a delay in epiboly, depleted S1P levels, elevated levels of sphingosine, and resistance to sphingosine toxicity. The sphk2MZ embryos also have strikingly increased levels of maternal transcripts encoding ceramide synthase 2b (Cers2b), and loss of Cers2b in sphk2MZ embryos phenocopies sphingosine toxicity. An upstream region of the cers2b promoter supports enhanced expression of a reporter gene in sphk2MZ embryos compared to wildtype embryos. Furthermore, ectopic expression of Cers2b protein itself reduces activity of the promoter, and this repression is relieved by exogenous sphingosine. Therefore, the sphk2MZ genome recognizes the lack of sphingosine kinase activity and up-regulates cers2b as a salvage pathway for sphingosine turnover. Cers2b can also function as a sphingolipid-responsive factor to mediate at least part of a feedback regulatory mechanism

The experience of living with knee osteoarthritis: exploring illness and treatment beliefs through thematic analysis

Purpose: Knee osteoarthritis (OA) is a major cause of disability in older adults. However, there is limited research on the daily experience of living with knee OA. We aimed to offer insight into the beliefs of patients with knee OA about their illness and treatment. Method: Twenty-four semi-structured interviews were conducted with 17 women and 7 men with physician-diagnosed knee OA, aged between 48 and 84 years (mean 1/4 62, SD 1/4 7). The audio-taped interviews lasted from 30 min to 1 h, and were transcribed verbatim. The data were subjected to thematic analysis. The transcripts were independently coded by two researchers to increase reliability of coding. Results: Six themes were developed and two of these are examined in further detail: (i) Illness representation and (ii) Beliefs about the medical and surgical control of pain. Illness representation comprised beliefs about people’s understanding of OA and their pain experience, as well as expectations about the course of illness. The second theme presented experiences of limited pain relief and concerns about the use of drugs and surgery. Conclusion: Exploring illness representations and beliefs about medical and surgical control of pain may provide the basis for initiating psychological interventions for people with knee OA

A Forward Chemical Screen in Zebrafish Identifies a Retinoic Acid Derivative with Receptor Specificity

Background: Retinoids regulate key developmental pathways throughout life, and have potential uses for differentiation therapy. It should be possible to identify novel retinoids by coupling new chemical reactions with screens using the zebrafish embryonic model. Principal Findings: We synthesized novel retinoid analogues and derivatives by amide coupling, obtaining 80–92% yields. A small library of these compounds was screened for bioactivity in living zebrafish embryos. We found that several structurally related compounds significantly affect development. Distinct phenotypes are generated depending on time of exposure, and we characterize one compound (BT10) that produces specific cardiovascular defects when added 1 day post fertilization. When compared to retinoic acid (ATRA), BT10 shows similar but not identical changes in the expression pattern of embryonic genes that are known targets of the retinoid pathway. Reporter assays determined that BT10 interacts with all three RAR receptor sub-types, but has no activity for RXR receptors, at all concentrations tested. Conclusions: Our screen has identified a novel retinoid with specificity for retinoid receptors. This lead compound may be useful for manipulating components of retinoid signaling networks, and may be further derivatized for enhanced activity

Discriminating neutrino mass models using Type II seesaw formula

In this paper we propose a kind of natural selection which can discriminate the three possible neutrino mass models, namely the degenerate, inverted hierarchical and normal hierarchical models, using the framework of Type II seesaw formula. We arrive at a conclusion that the inverted hierarchical model appears to be most favourable whereas the normal hierarchical model follows next to it. The degenerate model is found to be most unfavourable. We use the hypothesis that those neutrino mass models in which Type I seesaw term dominates over the Type II left-handed Higgs triplet term are favoured to survive in nature.Comment: No change in the results, a few references added, some changes in Type[IIB] calculation

Novel Retinoic Acid Receptor Alpha Agonists for Treatment of Kidney Disease

Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN