Increase In Poly Research Articles

Interplay between histone acetylation/deacetylation and poly(ADP-ribosyl)ation in the development of ischemic tolerance in vitro

Ischemic tolerance is an endogenous defense program in which exposure to a subtoxic preconditioning insult results in resistance to a subsequent, otherwise lethal, episode of ischemia. Herein, we evaluated the role of histone acetylation/deacetylation in an in vitro model of preconditioning, using rat organotypic hippocampal slices exposed to 30 min oxygen-glucose deprivation (OGD), which leads to CA1 injury 24 h later: tolerance was induced by exposing the slices to preconditioning bouts of NMDA (3 μM for 60 min) 24 h prior to the toxic OGD challenge. Under these conditions, CA1 damage induced by OGD was reduced. The induction of tolerance was prevented by incubating the slices with HDAC inhibitors. NMDA preconditioning was associated with a mild increase in poly(ADP-ribose) polymerase (PARP) activity that was apparently followed, 3 h later, by a mild increase in histone acetylation. Use of PARP and HDAC inhibitors suggests a possible interaction between PARP and HDAC activities in the development of ischemic tolerance. Finally, both PARP and HDAC inhibitors were able to prevent the increase in pERK1/2 induced by NMDA preconditioning. We propose a model in which mild histone acetylation and PARP activity cooperate in producing a neuroprotective response in the development of ischemic tolerance.

Zinc carnosine protects against hydrogen peroxide-induced DNA damage in WIL2-NS lymphoblastoid cell line independent of poly (ADP-Ribose) polymerase expression.

The aim of this study is to investigate the ability of zinc carnosine to protect the human lymphoblastoid (WIL2-NS) cell line from hydrogen peroxide-induced DNA damage. Cells were cultured with medium containing zinc carnosine at the concentrations of 0.4, 4, 16 and 32 μM for 9 days prior to treatment with 30 μM of hydrogen peroxide (30 min). Zinc carnosine at the concentration 16 μM was optimal in protecting cells from hydrogen peroxide-induced cytotoxicity and gave the lowest percentage of apoptotic and necrotic cells. Results showed that zinc carnosine was able to induce glutathione production and protect cells from hydrogen peroxide-induced oxidative stress at all concentration and the highest protection was observed at 32-μM zinc carnosine culture. Cytokinesis-block micronucleus cytome assay showed that cells cultured with 4-32 μM of zinc carnosine showed significant reduction in micronuclei formation, nucleoplasmic bridges and nuclear bud frequencies (p < 0.05), suggesting that these concentrations maybe optimal in protecting cells from hydrogen peroxide-induced DNA damage. However, after being challenged with hydrogen peroxide, no increase in poly(ADP-ribose) polymerase expression was observed. Thus, results from this study demonstrate that zinc carnosines possess antioxidant properties and are able to reduce hydrogen peroxide-induced DNA damage in vitro independent of poly(ADP-ribose) polymerase. Further studies are warranted to understand the mechanism of protection of zinc carnosine against hydrogen peroxide-induced damage.

Poly(ADP-ribose) polymerase activation mediates synchrotron radiation X-ray-induced damage of rodent testes by exacerbating DNA damage and apoptotic changes

Purposes: Synchrotron radiation (SR) X-ray has great potential for cancer treatment and medical imaging. It is of significance to investigate the mechanisms underlying the effects of SR X-ray irradiation on biological tissues, and search for the strategies for preventing the damaging effects of SR X-ray irradiation on normal tissues. The major aim of our current study is to test our hypothesis that poly(ADP-ribose) polymerase (PARP) plays a significant role in SR X-ray-induced tissue damage.Methods and materials: The testes of rodents were pre-treated with PARP inhibitor 3-aminobenzamide (3-AB) or antioxidant N-acetyl-acetylcysteine (NAC), followed by SR X-ray irradiation. PARP activation, double-strand DNA breaks (DSB), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) signals, caspase-3 activity and weight of the testes were determined.Results: SR X-ray irradiation produced dose-dependent increases in poly(ADP-ribose) (PAR) formation – an index of PARP activation, which can be prevented by NAC administration. Administration of 10 or 20 mg/kg 3-AB attenuated a variety of tissue injury induced by SR X-ray, including caspase-3 activation, increases in TUNEL signals and loss of testical weight. The PARP inhibitor also significantly decreased SR X-ray-induced γ-H2AX signal – a marker of DSB.Conclusions: Our study has provided the first evidence suggesting that SR X-ray can induce PARP activation by generating oxidative stress, which leads to various tissue injuries at least partially by exacerbating DNA damage and apoptotic changes.

Diabetes and Microvascular Dysfunction

Microvascular reactivity is an important mechanism that regulates local blood flow and therefore tissue perfusion. The reactivity (vasorelaxation and vasoconstriction) of microvessels is mainly regulated by mechanical factors (shear stress for relaxation and blood pressure for myogenic tone, which is a vasoconstriction of microvessels in response to increase in intraluminal blood pressure) and neurohormones. We previously showed that epidermal growth factor receptor tyrosine kinase (EGFRtk) is an important factor in the regulation of myogenic tone in microvessels. In fact, pressure-induced myogenic tone in resistance arteries is regulated by the mechanism that involves metalloproteinases 2 and 9 activation with subsequent Heparin-BindingEGF release and EGFRtk transactivation [1]. This mechanism appears to be specific to myogenic tone, since the contractions to angiotensin and KCl are independent of EGFRtk transactivation. We previously reported that diabetes is associated with microvascular dysfunction [1,2]. We observed reduced microvascular endothelium-dependent relaxation and aberrant increase in pressure-induced myogenic tone in type 2 diabetes [3,4]. The impairment in microvascular function in type 2 diabetes is, in part, caused by the enhanced EGFRtk activity. In a murine model of type 2 diabetic mice, we found an increase of EGFRtk phosphorylation in microvessels. Interestingly, the inhibition of EGFRtk improves vascular function in type 2 diabetes independently of the diabetes and obesity [4]. We also demonstrated that advanced glycation end products cause microvascular dysfunction in type 2 diabetes through the enhance in oxidative stress [3]. In another study, we demonstrated an increase in poly (ADP-ribose) polymerase 1 (PARP1) and nuclear factor-κB activity in microvessels isolated from type 2 diabetic compared to control [2,5,6]. Interestingly, the inhibition of PARP-1 and NFκB pathways improves microvascular function in type 2 diabetic mice [2,6] indicating that PARP-1 and NFκB are important factors in microvascular dysfunction in type 2 diabetes. The aberrant increase in PARP-1 and NFκB activity is caused by the augmented EGFRtk activity [2,7]. Thus, we determined that the inhibition of EGFRtk activity improved microvascular function by PARP-1 and NFκB-dependent mechanism [2,7] suggesting that EGFRtk is up stream to PARP-1 and NFκB signaling. The aberrant increase in NFκB and PARP-1 activity impairs microvascular function in type 2 diabetes by Sp-1 and COX-2-dependent mechanism. In summary, our studies delineated the mechanism of type 2 diabetes induced microvascular dysfunction. Therefore, the EGFRtk, oxidative stress, NFκB and PARP1 pathways could be potential targets for novel therapeutic strategies to overcome diabetes-induced microvascular dysfunction.

Caspase inhibition augments Dichlorvos-induced dopaminergic neuronal cell death by increasing ROS production and PARP1 activation

Numerous epidemiological studies have shown an association between pesticide exposure and the increased risk of developing Parkinson’s disease. Previously we have reported that Dichlorvos exposure can induce oxidative stress, resulting in over-expression of pro-apoptotic genes and finally caspase-dependent nigrostriatal dopaminergic neuronal cell death in rat brain. Here, we examined the effect of caspase inhibition on PC12 cell death induced by Dichlorvos (30μM). Reactive oxygen species (ROS) generation followed by protein carbonylation, lipid peroxidation, decreased antioxidant defenses (decreased Mn-superoxide dismutase (MnSOD) activity and decreased glutathione levels) and subsequent caspase activation mediated the apoptosis. Inhibition of caspase cascade with Boc-aspartyl(OMe)-fluoromethylketone (BAF) enhanced the Dichlorvos-induced PC12 cell death, as assessed by the increased cellular efflux of lactate dehydrogenase (LDH). This increase in cell death was accompanied by a marked increase in poly(ADP-ribose) polymerase-1 (PARP1) activity, increased oxidative stress, a reduction in the mitochondrial membrane potential and reduced cellular NAD and ATP levels. Pretreatment of cells with PJ34, a PARP1 inhibitor prevented the cells from undergoing cell death and preserved intracellular NAD and ATP levels. Subsequent release of the apoptosis-inducing factor (AIF) from mitochondria and its translocation into the nucleus was also prevented by PJ34 pretreatment. In conclusion, the results of the present study show that caspase inhibition without concurrent inhibition of PARP1 is unlikely to be effective in preventing cell death because in the presence of the caspase inhibitor, caspase-independent cell death predominates due to PARP activation. These results suggest that combined therapeutic strategies directed at multiple cell death pathways may provide superior neuroprotection than those directed at a single mechanism.

Performance of hydrocarbon particles on the drying shrinkage of cement mortar

The inherent volume reduction normally witnessed in hydraulic cement mixes is probably one of the most important threats to its durability as this is often accompanied by deleterious cracks. This paper presents experimental findings on the drying shrinkage of poly(1,4-isoprene) modified-hydraulic cement mortar. Based on mechanical and durability requirements 0–20% (vol.) isoprene/water ratio was employed. Normal and modified mortar specimens were prepared, cured and tested for drying shrinkage. Microstructural details of both normal and modified phases were examined through scanning electron microscopy (SEM). In addition, compressive strengths of the hardened mixes and thermogravimetry analysis (TGA) of the poly(1,4-isoprene) were noted. Results have indicated a continuous decrease in the drying shrinkage of mortar with a corresponding increase in poly(1,4-isoprene) up to 10% (vol.) isoprene/water ratio, beyond which the shrinkage increases with increase in the isoprene content. Thus, inclusion of optimum content of poly(1,4-isoprene) into the normal hydraulic cement mortar minimizes its drying shrinkage, principally due to blocking effects of the isoprene particles against the inter-particle attraction of the mixed-conglomerate during the volume reduction. Indeed, this could inhibit formation and propagation of harmful cracks.

Poly(2-(dimethylamino)ethyl methacrylate) brushes fabricated by surface-mediated RAFT polymerization and their response to pH

In this study, well-defined, high density poly(2-(dimethylamino)ethyl methacrylate) [poly(DMAEMA)] brushes were fabricated by the combination of the self-assembly of a monolayer of RAFT agent and surface-mediated RAFT polymerization. The whole fabrication process of the poly(DMAEMA) was followed by water contact angles, grazing angle-Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and atomic force microscopy. Kinetic studies revealed a linear increase in poly(DMAEMA) film thickness with polymerization time, indicating that the chain growth from the surface was a controlled process. Characterization of the poly(DMAEMA) brushes, such as molecular weight and thickness determination, were measured by gel permeation chromatography, and ellipsometry, and the grafting density was estimated. The pH response of the poly(DMAEMA) brushes was further investigated and the results verified the “brush-like” to “mushroom-like” transition of the poly(DMAEMA) chains due to the reversible protonation/deprotonation upon changing the solution pH.

Synthesis and properties of poly(3-n-dodecylthiophene) modified thermally expandable microspheres

Functionalization of thermally expandable microspheres (TEMs) with a conjugated polymer is explored. These functionalized thermally expandable microspheres were prepared by grafting 3-n-dodecylthiophene via oxidative polymerization from a thiophene modified TEM. The thiophene modified TEM to 3-n-dodecylthiophene ratio was varied during grafting and the resulting poly(3-n-dodecylthiophene) grafted TEM were characterized by FT-IR spectroscopy, Thermal Gravimetric Analysis, Scanning Electron Microscopy, Thermo-Mechanical Analysis and X-ray diffraction. The particles were approximately 30μm in diameter and upon heating, the functionalized microspheres expanded up to 50 times. This expansion property was related to the poly(3-n-dodecylthiophene) content, where the increase in poly(3-n-dodecylthiophene) on microsphere decreased the thermal expansion. The X-ray diffraction shows a sharpening of the poly(3-n-dodecylthiophene) (100) diffraction peak upon expansion. Grafting conjugated polymers to thermally expandable microspheres provides robust functional photo- and electro-active TEMs.

Preparation and characterization of poly(3-octyl thiophene)/polyvinyl chloride polymer blends

Different weight ratios of poly(3-octyl thiophene) / polyvinyl chloride blends were prepared using the casting method by dissolving poly(3-octyl thiophene) and polyvinyl chloride polymers in chloroform and Tetrahydrofuran, respectively. Fourier transform infrared spectroscopy indicates the existence of carbonyl group in both polyvinyl chloride neat and poly(3-octyl thiophene)–polyvinyl chloride blends. Electrical measurements reveal that the impedance values are increased with the increasing of both weight fraction of poly(3-octyl thiophene) and temperature. Optical results reveal that the increase of poly(3-octyl thiophene) weight fraction in blends enhances the UV-visible absorption of polyvinyl chloride and reduces the optical energy gap of blends. Differential scanning calorimetric measurements and thermal gravimetric analysis show that the glass transition temperature value and thermal stability of blend increases with increasing of poly(3-octyl thiophene) weight ratio. The obtained results, generally, indicate that the increase of poly(3-octyl thiophene) weight fraction enhances the interaction between poly(3-octyl thiophene)–polyvinyl chloride chains and as a result will restrict the chain mobility of polymers.

Minocycline Blocks Asthma-associated Inflammation in Part by Interfering with the T Cell Receptor-Nuclear Factor κB-GATA-3-IL-4 Axis without a Prominent Effect on Poly(ADP-ribose) Polymerase

Minocycline protects against asthma independently of its antibiotic function and was recently reported as a potent poly(ADP-ribose) polymerase (PARP) inhibitor. In an animal model of asthma, a single administration of minocycline conferred excellent protection against ovalbumin-induced airway eosinophilia, mucus hypersecretion, and Th2 cytokine production (IL-4/IL-5/IL-12(p70)/IL-13/GM-CSF) and a partial protection against airway hyperresponsiveness. These effects correlated with pronounced reduction in lung and sera allergen-specific IgE. A reduction in poly(ADP-ribose) immunoreactivity in the lungs of minocycline-treated/ovalbumin-challenged mice correlated with decreased oxidative DNA damage. The effect of minocycline on PARP may be indirect, as the drug failed to efficiently block direct PARP activation in lungs of N-methyl-N'-nitro-N-nitroso-guanidine-treated mice or H(2)O(2)-treated cells. Minocycline blocked allergen-specific IgE production in B cells potentially by modulating T cell receptor (TCR)-linked IL-4 production at the mRNA level but not through a modulation of the IL-4-JAK-STAT-6 axis, IL-2 production, or NFAT1 activation. Restoration of IL-4, ex vivo, rescued IgE production by minocycline-treated/ovalbumin-stimulated B cells. IL-4 blockade correlated with a preferential inhibition of the NF-κB activation arm of TCR but not GSK3, Src, p38 MAPK, or ERK1/2. Interestingly, the drug promoted a slightly higher Src and ERK1/2 phosphorylation. Inhibition of NF-κB was linked to a complete blockade of TCR-stimulated GATA-3 expression, a pivotal transcription factor for IL-4 expression. Minocycline also reduced TNF-α-mediated NF-κB activation and expression of dependent genes. These results show a potentially broad effect of minocycline but that it may block IgE production in part by modulating TCR function, particularly by inhibiting the signaling pathway, leading to NF-κB activation, GATA-3 expression, and subsequent IL-4 production.

Zn2+‐induced ERK activation mediates PARP‐1‐dependent ischemic‐reoxygenation damage to oligodendrocytes

Much of the cell death following episodes of anoxia and ischemia in the mammalian central nervous system has been attributed to extracellular accumulation of glutamate and ATP, which causes a rise in [Ca(2+)](i), loss of mitochondrial potential, and cell death. However, restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury (the oxygen paradox). Herein we describe a novel signaling pathway that is activated during ischemia-like conditions (oxygen and glucose deprivation; OGD) and contributes to ischemia-induced oligodendroglial cell death. OGD induced a retarded and sustained increase in extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation after restoring glucose and O(2) (reperfusion-like conditions). Blocking the ERK1/2 pathway with the MEK inhibitor UO126 largely protected oligodendrocytes against ischemic insults. ERK1/2 activation was blocked by the high-affinity Zn(2+) chelator TPEN, but not by antagonists of AMPA/kainate or P2X7 receptors that were previously shown to be involved in ischemic oligodendroglial cell death. Using a high-affinity Zn(2+) probe, we showed that ischemia induced an intracellular Zn(2+) rise in oligodendrocytes, and that incubation with TPEN prevented mitochondrial depolarization and ROS generation after ischemia. Accordingly, exposure to TPEN and the antioxidant Trolox reduced ischemia-induced oligodendrocyte death. Moreover, UO126 blocked the ischemia-induced increase in poly-[ADP]-ribosylation of proteins, and the poly[ADP]-ribose polymerase 1 (PARP-1) inhibitor DPQ significantly inhibited ischemia-induced oligodendroglial cell death-demonstrating that PARP-1 was required downstream in the Zn(2+)-ERK oligodendrocyte cell death pathway. Chelation of cytosolic Zn(2+), blocking ERK signaling, and antioxidants may be beneficial for treating CNS white matter ischemia-reperfusion injury. Importantly, all the inhibitors of this pathway protected oligodendrocytes when applied after the ischemic insult.

Spirooxindole Derivative SOID-8 Induces Apoptosis Associated with Inhibition of JAK2/STAT3 Signaling in Melanoma Cells

Melanoma is generally refractory to current chemotherapy, thus new treatment strategies are needed. In this study, we synthesized a series of spirooxindole derivatives (SOID-1 to SOID-12) and evaluated their antitumor effects on melanoma. Among the 12 spirooxindole derivatives, SOID-8 showed the strongest antitumor activity by viability screening. SOID-8 inhibited viability of A2058, A375, SK-MEL-5 and SK-MEL-28 human melanoma cells in a dose- and time-dependent manner. SOID-8 also induced apoptosis of these tumor cells, which was confirmed by positive Annexin V staining and an increase of poly(ADP-ribose) polymerase cleavage. The antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was downregulated and correlated with SOID-8 induced apoptosis. In addition, SOID-8 reduced tyrosine phosphorylation of Signal Tansducer and Activator of Transcription 3 (STAT3) in both dose- and time-dependent manners. This inhibition was associated with decreased levels of phosphorylation of Janus-activated kinase-2 (JAK2), an upstream kinase that mediates STAT3 phosphorylation at Tyr705. Accordingly, SOID-8 inhibited IL-6-induced activation of STAT3 and JAK2 in melanoma cells. Finally, SOID-8 suppressed melanoma tumor growth in a mouse xenograft model, accompanied with a decrease of phosphorylation of JAK2 and STAT3. Our results indicate that the antitumor activity of SOID-8 is at least partially due to inhibition of JAK2/STAT3 signaling in melanoma cells. These findings suggest that the spirooxindole derivative SOID-8 is a promising lead compound for further development of new preventive and therapeutic agents for melanoma.

CDK2-dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells

Eukaryotic gene regulation implies that transcription factors gain access to genomic information via poorly understood processes involving activation and targeting of kinases, histone-modifying enzymes, and chromatin remodelers to chromatin. Here we report that progestin gene regulation in breast cancer cells requires a rapid and transient increase in poly-(ADP)-ribose (PAR), accompanied by a dramatic decrease of cellular NAD that could have broad implications in cell physiology. This rapid increase in nuclear PARylation is mediated by activation of PAR polymerase PARP-1 as a result of phosphorylation by cyclin-dependent kinase CDK2. Hormone-dependent phosphorylation of PARP-1 by CDK2, within the catalytic domain, enhances its enzymatic capabilities. Activated PARP-1 contributes to the displacement of histone H1 and is essential for regulation of the majority of hormone-responsive genes and for the effect of progestins on cell cycle progression. Both global chromatin immunoprecipitation (ChIP) coupled with deep sequencing (ChIP-seq) and gene expression analysis show a strong overlap between PARP-1 and CDK2. Thus, progestin gene regulation involves a novel signaling pathway that connects CDK2-dependent activation of PARP-1 with histone H1 displacement. Given the multiplicity of PARP targets, this new pathway could be used for the pharmacological management of breast cancer.

Nanocomposites of Carbonated Hydroxyapatite/Poly (4-vinyl pyridine-co-styrene): Synthesis, Characterization and its Application

nanocarbonated hydroxyapatite/Poly (4-vinyl pyridine-co-styrene) composites of varying composition for biomaterial applications have been synthesized. The nanocarbonated hydroxyapatite/Poly (4-vinyl pyridine-co-styrene) composite materials were characterized by XRD, FTIR, 31P NMR, TGA, DTA and FESEM. Carbonated Hydroxyapatite nanorod embedded composite was prepared using Poly (4-vinyl pyridine-co-styrene) as a matrix with different weight percentages (wt %). The results indicated that the size and crystallinity of Carbonated hydroxyapatite nanoparticles decreases with increase in Poly (4-vinyl pyridine-co-styrene) concentration in the composite. SEM confirms the presence of carbonated hydroxyapatite nanorod crystals in Poly (4-vinyl pyridine-co-styrene) matrix. nanoCarbonated hydroxyapatite/ Poly (4-vinyl pyridine-co-styrene) composites were screened for antimicrobial activity and anti inflammatory activity.

Time Profile of Oxidative Stress and Neutrophil Activation in Ovine Acute Lung Injury and Sepsis

The formation of oxidative stress in the lung and activation of neutrophils are major determinants in the development of respiratory failure after acute lung injury and sepsis. However, the time changes of these pathogenic factors have not been sufficiently described. Twenty-four chronically instrumented sheep were subjected to cotton smoke inhalation injury and instillation of live Pseudomonas aeruginosa into both lungs. The sheep were euthanized at 4, 8, 12, 18, and 24 h after injury. Additional sheep received sham injury and were euthanized after 24 h. Pulmonary function was assessed by determination of oxygenation index and pulmonary shunt fraction. In addition, lung tissue was harvested at the respective time points for the measurement of malondialdehyde, interleukin 6, poly(ADP ribose), myeloperoxidase, and alveolar polymorphonuclear neutrophil score. The injury induced severe respiratory failure that was associated with an early increase in lipid peroxidation and interleukin 6 expression. The injury further led to an increase in poly(ADP ribose) activity that reached its peak at 12 h after injury and declined afterward. In addition, progressive increases in markers of neutrophil accumulation in the lung were observed. The peak of neutrophil accumulation in the lung was associated with a severe depletion of circulating neutrophils. The results from our model may enhance the understanding of the pathophysiological alterations after acute lung injury and sepsis and thus be useful in exploring therapeutic interventions directed at modifying the expression or activation of inflammatory mediators.

Morphology and Surface Properties of Poly (L-lactic acid)/Captopril Composite Nanofiber Membranes

In this study, Poly (L-lactic acid)/Captopril composite nanofiber membranes were electrospun for drug delivery. Different mass fractions of Poly (L-lactic acid), different ratios of Captopril and the influences of PEG4000 added in the spinning solution are discussed. The morphology, chemical components, the surface areas and pore sizes, wettability of the composite nanofiber membranes were investigated. The results showed that the diameters of the composite nanofibers increased with the increase of Poly (L-lactic acid) mass fractions, the diameters decreased with the increase of Captopril content as well as the addition of the surfactant. Fourier Transform Infrared (FT-IR) showed the chemical components of Captopril remained unchanged when it was electrospun into the composite nanofibers. The surface areas pore width and pore volume of the composite nanofibers became a little larger than those of poly (L-lactic acid) nanofibers, and the wettability of the composite nanofiber membranes was better than those of poly (L-lactic acid) nanofiber membranes. Wettability was improved by an increase of the drug load amount.

Mobility increase in poly [2-methoxy-5-(2′-ethylhexyloxy)-1, 4-phenylenevinylene] blended with graphene

Poly [2-methoxy-5-(2′-ethylhexyloxy)-1, 4-phenylenevinylene] (MEH-PPV) is an important polymer material. However, the low carrier mobility of MEH-PPV limits its applications. Graphene is a two dimensional material with very high carrier mobility. In this letter, we report increasing the mobility of MEH-PPV by blending it with graphene nanosheets synthesized by the arc discharge method. Both the hole and electron mobilities of MEH-PPV blended with graphene nanosheets increase monotonically with the blending content. The increase can be as high as one order of magnitude at blending content of about 2.5%. Little fluorescence quenching is observed in the graphene blended MEH-PPV.

Biodegradable amphiphiles of grafted poly(lactide) onto 2‐hydroxyethyl methacrylate‐co‐N‐vinylpyrrolidone copolymers as drug carriers

AbstractThis article describes the synthesis and characterization of 2‐hydroxylethyl methacrylate‐co‐N‐vinylpyrrolidone copolymers, (HEMA‐co‐NVP), via free radical polymerization followed by grafting of poly(lactide) onto (HEMA‐co‐NVP) copolymers, via ring opening polymerization using tin octoate as a catalyst. The copolymers and the grafted copolymers (i.e., amphiphiles) were subjected to sustained release studies using salicylic acid, as a model drug. Characterization of the formed copolymers was performed using 1H‐NMR, 13C‐NMR, FTIR, TGA, DSC, and SEM techniques. Derivative of TGA thermogram was used to determine %hydrophilicity and %hydrophobicity in the grafted and ungrafted copolymers. The SEM morphology revealed porous layers with crispy structure that were most likely due to the presence of poly(lactide) chains. At lower content of poly(lactide) moiety, grafted copolymers showed non‐Fickian diffusion release rate, whereas Fickian diffusion release rate at higher content of poly(lactide) was observed. The increase of poly(lactide) content (i.e., larger %hydrophobicity) in the copolymer increased the drug‐sustainability, due to the consistent but porous amphiphilic degradable structures that allow controllable release of drug in time interval. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

Abstract 5432: Spirooxindole derivative (SOID-8) inhibits proliferation and induces apoptosis by blocking JAK2/STAT3 signaling in melanoma cells

Abstract Melanoma is the most malignant skin cancer, and is generally refractory to current chemotherapy, so new treatment strategies are needed. In this study, we show that a spirooxindole derivative, SOID-8, which is a synthetic analogue inspired by the natural product, spirotryprostatin B, significantly inhibits cell proliferation in four established human melanoma cell lines. This decrease in viability of A2058 and A375 melanoma cells is associated with apoptosis, as confirmed by an increase in poly(ADP-ribose)polymerase cleavage. In addition, the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, is downregulated and correlated with SOID-8 induced apoptosis. Morevoer, SOID-8 inhibits tyrosine phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) in both melanoma cell lines in a dose- and time-dependent manner. In contrast, phosphorylation of AKT (protein kinase B) is reduced by SOID-8 only at high concentrations, and phosphorylation of MAPK (extracellular signal-regulated kinase 1/2) is not inhibited at all by SOID-8 in these cells. Furthermore, this compound decreases the phosphorylated Janus kinase-2 (JAK2) levels in a dose- and time-dependent fashion. Importantly, SOID-8 inhibits phosphorylation of STAT3 and JAK2 induced by IL-6 stimulation in A2058 and A375 cells. In summary, our results show that SOID-8 selectively blocks JAK2/STAT3 signaling as well as expression of apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in melanoma cells. These data suggest that antitumor activity of the spirooxindole derivative SOID-8 is at least partially due to inhibition of JAK2/STAT3 signaling in melanoma cells and is a promising small molecule candidate for melanoma therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5432. doi:10.1158/1538-7445.AM2011-5432

PARP inhibition prevents oxidative injury of bladder induced by acute urinary retention and subsequent emptying

It has been demonstrated that increases in poly(ADP-ribose) polymerase (PARP) activity causes damage to several organs under ischemia/reperfusion (I/R) conditions. The aims of this study were to investigate whether inhibition of PARP could suppress apoptosis in the bladder following acute urinary retention (AUR) and subsequent bladder emptying. Twelve-week-old male Sprague Dawley rats were divided into a control group, saline treated group, and 3-aminobenzamide (3-AB, a specific PARP inhibitor)-treated group. Sixty minutes after the administration of saline and 3-AB, the saline and 3-AB-treated groups had 60 min of over-distension and followed by 2 h of drainage. The degree of bladder apoptosis, levels of malondialdehyde (MDA), ATP and nicotinamide adenine dinucleotide (NAD+); expression of poly(ADP-ribose) (PAR), phosphorylation of protein kinase B (Akt); and levels of Bcl-2, Bax, and caspase 3 activity in the bladder were determined. Molecular and histological analyses showed that bladder apoptosis was associated with increases in the amount of PAR and decreases in ATP and NAD+ levels in the saline treated group. In addition, phosphorylated Akt and Bcl-2/Bax ratio were significantly decreased. The activity of caspase 3 was significantly increased in the saline treated group. Inhibition of PARP significantly increased the levels of ATP and NAD+, phosphorylation of Akt, and Bcl-2/Bax ratio, and significantly reduced the activation of caspase 3. As a result, apoptosis in the bladder was attenuated. These results indicate that PARP activation may be involved in apoptosis in the bladder induced by AUR and subsequent emptying via energy depletion and suppression of Akt activity.