14 research outputs found

    H<sub>2</sub>O<sub>2</sub>/Peroxynitrite-Activated Hydroxamic Acid HDAC Inhibitor Prodrugs Show Antileukemic Activities against AML Cells

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    Occurrence of acute myeloid leukemia (AML) results in abundant endogenous reactive oxygen species (ROS)/reactive nitrogen species (RNS) in AML cells and in disease-relevant microenvironments. Histone deacetylase inhibitor (HDACi) prodrug approach was designed accordingly by masking the hydroxamic acid zinc binding group with hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)/peroxynitrite (PNT)-sensitive, self-immolative aryl boronic acid moiety. Model prodrugs <b>5</b>–<b>82</b> and <b>5</b>–<b>23</b> were activated in AML cells to release cytotoxic HDACis, evidenced by inducing acetylation markers and reducing viability of AML cells. Intracellular activation and antileukemic activities of prodrug were increased or decreased by ROS/PNT inducers and scavengers, respectively. Prodrugs <b>5</b>–<b>82</b> and <b>5</b>–<b>23</b> also enhanced the potency of chemotherapy drug cytarabine, supporting the potentials of this prodrug class in combinatorial treatment

    Self-Assembly of Graphene Single Crystals with Uniform Size and Orientation: The First 2D Super-Ordered Structure

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    The challenges facing the rapid developments of highly integrated electronics, photonics, and microelectromechanical systems suggest that effective fabrication technologies are urgently needed to produce ordered structures using components with high performance potential. Inspired by the spontaneous organization of molecular units into ordered structures by noncovalent interactions, we succeed for the first time in synthesizing a two-dimensional superordered structure (2DSOS). As demonstrated by graphene, the 2DSOS was prepared via self-assembly of high-quality graphene single crystals under mutual electrostatic force between the adjacent crystals assisted by airflow-induced hydrodynamic forces at the liquid metal surface. The as-obtained 2DSOS exhibits tunable periodicity in the crystal space and outstanding uniformity in size and orientation. Moreover, the intrinsic property of each building block is preserved. With simplicity, scalability, and continuously adjustable feature size, the presented approach may open new territory for the precise assembly of 2D atomic crystals and facilitate its application in structurally derived integrated systems

    Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy

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    Learning and memory deficits in Alzheimer’s disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described that uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABA<sub>A</sub> receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen–glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for restoration of synaptic function in hippocampal slices from AD-transgenic mice, reversal of cognitive deficits, and brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together, the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD

    Zwitterionic-Modified Starch-Based Stealth Micelles for Prolonging Circulation Time and Reducing Macrophage Response

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    Over the last few decades, nanoparticles have been emerging as useful means to improve the therapeutic efficacy of drug delivery and medical diagnoses. However, the heterogeneity and complexity of blood as a medium is a fundamental problem; large amounts of protein can be adsorbed onto the surface of nanoparticles and cause their rapid clearance before reaching their target sites, resulting in the failure of drug delivery. To overcome this challenge, we present a rationally designed starch derivative (SB-ST-OC) with both a superhydrophilic moiety of zwitterionic sulfobetaine (SB) and a hydrophobic segment of octane (OC) as functional groups, which can self-assemble into “stealth” micelles (SSO micelles). The superhydrophilic SB kept the micelles stable against aggregation in complex media and imbued them with “stealth” properties, eventually extending their circulation time in blood. In stability and hemolysis tests the SSO micelles showed excellent protein resistance properties and hemocompatibility. Moreover, a phagocytosis test and cytokine secretion assay confirmed that the SSO micelles had less potential to trigger the activation of macrophages and were more suitable as a drug delivery candidate <i>in vivo</i>. On the basis of these results, doxorubicin (DOX), a hydrophobic drug, was used to investigate the potential application of this novel starch derivative <i>in vivo</i>. The results of the pharmacokinetic study showed that the values of the plasma area under the concentration curve (AUC) and elimination half-life (<i>T</i><sub>1/2</sub>) of the SSO micelles were higher than those of micelles without SB modifications. In conclusion, the combination of excellent protein resistance, lower macrophage activation, and longer circulation time <i>in vivo</i> makes this synthesized novel starch derivative a promising candidate as a hydrophobic drug carrier for long-term circulation <i>in vivo.</i

    An NO Donor Approach to Neuroprotective and Procognitive Estrogen Therapy Overcomes Loss of NO Synthase Function and Potentially Thrombotic Risk

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    <div><p>Selective estrogen receptor modulators (SERMs) are effective therapeutics that preserve favorable actions of estrogens on bone and act as antiestrogens in breast tissue, decreasing the risk of vertebral fractures and breast cancer, but their potential in neuroprotective and procognitive therapy is limited by: 1) an increased lifetime risk of thrombotic events; and 2) an attenuated response to estrogens with age, sometimes linked to endothelial nitric oxide synthase (eNOS) dysfunction. Herein, three 3<sup>rd</sup> generation SERMs with similar high affinity for estrogen receptors (ERα, ERβ) were studied: desmethylarzoxifene (DMA), FDMA, and a novel NO-donating SERM (NO-DMA). Neuroprotection was studied in primary rat neurons exposed to oxygen glucose deprivation; reversal of cholinergic cognitive deficit was studied in mice in a behavioral model of memory; long term potentiation (LTP), underlying cognition, was measured in hippocampal slices from older 3×Tg Alzheimer's transgenic mice; vasodilation was measured in rat aortic strips; and anticoagulant activity was compared. Pharmacologic blockade of GPR30 and NOS; denudation of endothelium; measurement of NO; and genetic knockout of eNOS were used to probe mechanism. Comparison of the three chemical probes indicates key roles for GPR30 and eNOS in mediating therapeutic activity. Procognitive, vasodilator and anticoagulant activities of DMA were found to be eNOS dependent, while neuroprotection and restoration of LTP were both shown to be dependent upon GPR30, a G-protein coupled receptor mediating estrogenic function. Finally, the observation that an NO-SERM shows enhanced vasodilation and anticoagulant activity, while retaining the positive attributes of SERMs even in the presence of NOS dysfunction, indicates a potential therapeutic approach without the increased risk of thrombotic events.</p></div

    SERM reversal of memory deficits in WT mice is retained by NO-DMA in eNOS (−/−) mice.

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    <p>Amnestic memory deficit was induced by i.p. injection of either scopolamine (1 mg/kg) or L-NAME (50 mg/kg) 30 min prior to training in C57Bl/6 male mice. SERMs (2 mg/kg) were given 20 min prior to training and latency was assessed 24 h after training with animals being removed from the task if latency >300 s. All SERMs, except F-DMA, restored scopolamine-induced deficits in STPA in C57Bl/6 animals. Against L-NAME-induced deficit, only NO-DMA showed efficacy in reversing memory deficits. In eNOS (−/−) animals subject to scopolamine-induced amnesia, only NO-DMA showed efficacy. Data show mean and S.E.M. (n = 4–10); *** = p<0.001 compared to non-insult wild type vehicle control using one-way ANOVA with Dunnett's post hoc test; F<sub>(14,124)</sub> = 29.26, p<0.0001.</p

    Relaxation of isolated aortic rings by SERMs and NO-SERM.

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    <p>(<b>A</b>) The EC<sub>50</sub> values for relaxation were not significantly different for raloxifene, arzoxifene, DMA, and FDMA (p>0.05, one-way ANOVA and Newman-Keul's post-hoc test), whereas for NO-DMA potency was significantly different from all other SERMs (F<sub>(4,43)</sub> = 4.085, p<0.01). The maximal relaxation responses for arzoxifene and FDMA were significantly less than those for DMA and raloxifene (F<sub>(3, 37)</sub> = 11.77 p<0.05, one-way ANOVA and Newman-Keul's post-hoc test). Each value represents the mean ± S.E.M. (n = 7–13). (<b>B</b>) Removal of the endothelium or inhibition of NOS with L-NAME reduced the maximal relaxation response to DMA (F<sub>(2, 18)</sub> = 28.22, p<0.001, one-way ANOVA and Newman-Keuls post-hoc test). Each value represents the mean ± S.E.M. (n = 7). (<b>C</b>) The EC<sub>50</sub> values for relaxation were significantly increased in the presence of L-NAME or after endothelium removal (F<sub>(2,18)</sub> = 7.753, p<0.05, one-way ANOVA and Newman-Keuls post-hoc test). Each value represents the mean ± S.E.M. (n = 7).</p

    Effects of SERM and NO-SERMon NO levels in plasma and brain of WT and eNOS (−/−) mice.

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    <p>Levels of NO were assessed by measuring breakdown products 1 h after i.p. injection of SERMs (2 mg/kg) using chemiluminescence detection. Both DMA and NO-DMA increased levels of NO in WT mice. The diminished response in eNOS (−/−) was significantly attenuated in DMA relative to NO-DMA treated animals. Data show mean and S.E.M. (n = 4–12); * = p<0.05, ** = p<0.01, *** = p<0.001 compared to wild type vehicle control using one-way ANOVA with Dunnett's post hoc test within each group: hippocampus F<sub>(4,40)</sub> = 7.79, p<0.0001; plasma F<sub>(4, 23)</sub> = 21.76, p<0.0001.</p

    Reversal of LTP deficit in aged 3×Tg mice by SERMs is GPR30 dependent.

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    <p>LTP was measured after TBS in the CA1 region of hippocampal sections from 16 month male 3×Tg mice or WT controls. Test compounds (SERMs 100 nM; G15 100 nM) were added 30 min prior to TBS. (<b>A, B</b>) DMA and NO-DMA restored deficits in LTP to WT levels and G15 blocked the actions of DMA. (<b>C</b>) Secondary analysis of theta bursts indicate action both during induction and stabilization of LTP, through a GPR30 dependent mechanism. Data show mean and S.E.M. normalized to baseline (n = 4–9); for end fEPSP: * = p<0.05, ** = p<0.01 compared to wild type transgenic background controls using one-way ANOVA with Dunnett's post hoc test; F<sub>(4,32)</sub> = 8.21, p = 0.0001.</p

    SERM-elicited neuroprotection in primary cortical neurons exposed to OGD is GPR30 dependent and retained by NO-DMA.

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    <p>Primary neuronal cultures were subjected to 2 h OGD with compounds added at the start of OGD and inhibitors added 45 min prior to OGD. Cell survival was measured at 24 h. Use of pathway-selective inhibitors indicates that neuroprotection of DMA and NO-DMA is mediated through PI3K-dependent GPR30 signaling in an ER- and NOS-independent manner. Data show mean and S.E.M. normalized to veh. control and estradiol (n = 6); * = p<0.05, ** = p<0.01, *** = p<0.001 compared to untreated vehicle control using one-way ANOVA with Dunnett's post hoc test within each treatment group; no blocker F<sub>(4,67)</sub> = 169.5, p<0.0001; ICI 182780 F<sub>(4,61)</sub> = 58.65, p<0.0001; pertussis F<sub>(4,61)</sub> = 6.78, p = 0.0001; G15 F<sub>(4,61)</sub> = 0.63, p = 0.64; LY294002 F<sub>(4,61)</sub> = 6.29, p<0.001; L-NAME F<sub>(4,61)</sub> = 89.33, p<0.0001.</p