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  • Identification of nitric oxide as an endogenous activator of the AMP-activated protein kinase in vascular endothelial cells

    Zhang, J; Xie, Z; Dong, Y; Wang, S; Liu, C; Zou, MH;
    Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    Product(s): A23187
    In endothelial cells, the AMP-activated protein kinase (AMPK) is stimulated by sheer stress or growth factors that stimulate release of nitric oxide (NO). We hypothesized that NO might act as an endogenous activator of AMPK in endothelial cells. Exposure of human umbilical vein endothelial cells (HUVECs) to NO donors caused an increase in phosphorylation of both Thr-172 of AMPK and Ser-1177 of endothelial nitric oxide synthase, a downstream enzyme of AMPK. NO-induced activation of AMPK was not affected by inhibition of LKB1, an AMPK kinase. In contrast, inhibition of calcium calmodulin-dependent protein kinase kinase abolished the effect of NO in HUVECs. NO-induced AMPK activation in HeLa S3 cells was abolished by either 1H-(1,2,4)-oxadiazole[4,3-a]quinoxalon-1-one, a potent inhibitor for guanylyl cyclase, or 1,2-bis(2-aminophenoxy)ethane-N,N,N ,N -tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), an intracellular Ca(2+) chelator, indicating that NO-induced AMPK activation is guanylyl cyclase-mediated and calcium-dependent. Exposure of HUVECs or isolated mice aortas to either calcium ionophore A23187 or bradykinin significantly increased AMPK Thr-172 phosphorylation, which was abolished by N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. Finally, A23187- or bradykinin-enhanced AMPK activation was significantly greater in aortas from wild type mice than those in the aortas of endothelial nitric oxide synthase knock-out mice. Taken together, we conclude that NO might act as an endogenous AMPK activator.
    10.1074/jbc.M802578200
  • Preparation, characterization, and biological analysis of liposomal formulations of vincristine

    Waterhouse, DN; Madden, TD; Cullis, PR; Bally, MB; Mayer, LD; Webb, MS;
    Department of Advanced Therapeutics, British Columbia Cancer Agency, British Columbia, Canada
    Product(s): A23187
    Vincristine is a dimeric Catharanthus alkaloid derived from the Madagascan periwinkle that acts by binding to tubulin and blocking metaphase in actively dividing cells. While vincristine is widely used in the treatment of a number of human carcinomas, its use is associated with dose-limiting neurotoxicity, manifested mainly as peripheral neuropathy. It is known that the therapeutic activity of vincristine can be significantly enhanced after its encapsulation in appropriately designed liposomal systems. Enhanced efficacy is also associated with a slight decrease in drug toxicity. Thus, the therapeutic index of vincristine can be enhanced significantly through the use of a liposomal delivery system. Vincristine may be encapsulated into liposomes of varying lipid composition by several techniques, including passive loading, pH gradient loading, and ionophore-assisted loading. However, most research has focused on the encapsulation of vincristine in response to a transbilayer pH gradient, which actively concentrates the drug within the aqueous interior of the liposome. This chapter details the preparation and evaluation of liposomal vincristine. Specifically, we elaborate on the components (choice of lipids, molar proportions, etc.), methods (preparation of liposomes, drug loading methods, etc.), critical design features (size, surface charge, etc.), and key biological endpoints (circulation lifetime, bioavailability, efficacy measurements) important to the development of a formulation of vincristine with enhanced therapeutic properties.
    10.1016/S0076-6879(05)91002-1
  • Spermatozoa have decreased antioxidant enzymatic capacity and increased reactive oxygen species production during aging in the Brown Norway rat

    Weir, CP; Robaire, B;
    Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada
    Product(s): A23187
    As the proportion of aged males attempting to reproduce continues to rise, so does the concern regarding the quality of spermatozoa from aged men. An imbalance between the generation of reactive oxygen species (ROS) and cellular antioxidant defenses, as occurs in aging, ultimately leads to decreased protein, lipid, and DNA quality. Spermatozoa are highly susceptible to oxidative damage, and thus an age-related shift in redox status may have serious implications for fertility. Therefore, we examined the effect of age on antioxidant enzymatic activity, ROS production, and extent of lipid peroxidation in both caput and cauda epididymal spermatozoa from young (4-month-old) and old (21-month-old) Brown Norway rats. Glutathione peroxidase (Gpx1, Gpx4) and superoxide dismutase (SOD) enzymes had decreased activity in aging spermatozoa. Immunofluorescence studies indicated that Gpx4 expression was decreased in both the head and midpiece regions of spermatozoa in aged animals. The decrease in nuclear Gpx4 points to a novel potential mechanism that may explain the previously noted decreased levels of protamine disulfide bonds in aged sperm nuclei. Further, hydrogen peroxide (H2O2) and superoxide (O2(.-)) production were increased significantly in aging spermatozoa. Finally, lipid peroxidation was found to be drastically increased in aged spermatozoa. Taken together, these results suggest a decreased capacity for aged spermatozoa to handle oxidative stress and provide a potential basis for understanding the underlying cause of decreased quality of spermatozoa during aging.
    10.2164/jandrol.106.001362
  • THE BROWN NORWAY RAT

    Weir, C;
    Product(s): A23187
  • Calcium regulates the interaction of amyloid precursor protein with Homer3 protein

    Kyratzi, E; Efthimiopoulos, S;
    Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Ilisia, Athens, Greece
    Product(s): A23187
    Ca(2+) dysregulation is an important factor implicated in Alzheimer s disease pathogenesis. The mechanisms mediating the reciprocal regulation of Ca(2+) homeostasis and amyloid precursor protein (APP) metabolism, function, and protein interactions are not well known. We have previously shown that APP interacts with Homer proteins, which inhibit APP processing toward amyloid-β. In this study, we investigated the effect of Ca(2+) homeostasis alterations on APP/Homer3 interaction. Influx of extracellular Ca(2+) upon treatment of HEK293 cells with the ionophore A23187 or addition of extracellular Ca(2+) in cells starved of calcium specifically reduced APP/Homer3 but not APP/X11a interaction. Endoplasmic reticulum Ca(2+) store depletion by thapsigargin followed by store-operated calcium entry also decreased the interaction. Interestingly, application of a phospholipase C stimulator, which causes inositol 1,4,5-trisphosphate-induced endoplasmic reticulum Ca(2+) release, caused dissociation of APP/Homer3 complex. In human neuroblastoma cells, membrane depolarization also disrupted the interaction. This is the first study showing that changes in Ca(2+) homeostasis affect APP protein interactions. Our results suggest that Ca(2+) and Homers play a significant role in the development of Alzheimer s disease pathology. Copyright © 2014. Published by Elsevier Inc.
    10.1016/j.neurobiolaging.2014.03.019

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