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991.
Ronit Reich-Slotky Christina A. Kabbash Phyllis Della-Latta John S. Blanchard Steven J. Feinmark Sherry Freeman Gilla Kaplan Howard A. Shuman Samuel C. Silverstein 《Journal of bacteriology》2009,191(16):5262-5271
We report here that gemfibrozil (GFZ) inhibits axenic and intracellular growth of Legionella pneumophila and of 27 strains of wild-type and multidrug-resistant Mycobacterium tuberculosis in bacteriological medium and in human and mouse macrophages, respectively. At a concentration of 0.4 mM, GFZ completely inhibited L. pneumophila fatty acid synthesis, while at 0.12 mM it promoted cytoplasmic accumulation of polyhydroxybutyrate. To assess the mechanism(s) of these effects, we cloned an L. pneumophila FabI enoyl reductase homolog that complemented for growth an Escherichia coli strain carrying a temperature-sensitive enoyl reductase and rendered the complemented E. coli strain sensitive to GFZ at the nonpermissive temperature. GFZ noncompetitively inhibited this L. pneumophila FabI homolog, as well as M. tuberculosis InhA and E. coli FabI.The advent of AIDS and the emergence of many multidrug-resistant bacterial species have led to renewed efforts to find new antibiotics. The most commonly used antibiotics act by blocking bacterium-specific DNA, RNA, or protein synthesis. Mycobacterium tuberculosis is a major exception to this generalization. While streptomycin, an inhibitor of bacterial protein synthesis, was the first antibiotic to be used successfully to treat M. tuberculosis, isoniazid (INH), an inhibitor of mycobacterial lipid synthesis, is presently the drug most commonly used to treat infections with this organism (2, 43). The differential sensitivity to INH of M. tuberculosis versus mammalian cells reflects the fact that most bacterial fatty acid synthases (type II synthases) are comprised of discrete, separable enzymes encoded by separate genes, while mammalian fatty acid synthases (type I) are dimeric proteins in which a single polypeptide catalyzes the seven enzymatic activities of fatty acid synthesis (21, 52).In previous studies (45), we reported that gemfibrozil (GFZ), a commonly prescribed and well-tolerated hypolipidemic drug, inhibits the export of various organic anions, including penicillin and fluoroquinolones, from murine macrophages, thereby elevating the intracellular concentration of these antibiotics and enhancing their capacity to block intracellular growth of Listeria monocytogenes. In exploring this system, we discovered that while GFZ has no effect on axenic or intracellular growth of Listeria monocytogenes, it inhibits axenic growth of all Legionella pneumophila strains tested and of 5 wild-type and 22 multidrug-resistant strains of M. tuberculosis and inhibits intracellular growth of L. pneumophila Philadelphia-1 and M. tuberculosis H37RV in human and mouse macrophages, respectively.Both M. tuberculosis and L. pneumophila are facultative intracellular pathogens that enter host macrophages by phagocytosis (25, 26), grow in nonlysosomal membrane-bound cytoplasmic vacuoles (24), have special nutrient requirements (38, 54, 55), and produce a relatively unique spectrum of membrane lipids (7, 57). However, M. tuberculosis is a slow-growing and dangerous organism with which to work. In contrast, L. pneumophila has a relatively short doubling time (120 min) in axenic culture medium and requires no special biohazard precautions. Therefore, we explored the mechanism(s) responsible for GFZ''s antibiotic activity in L. pneumophila, in the expectation that a similar mechanism(s) would be operative in M. tuberculosis.We report here that GFZ noncompetitively inhibits L. pneumophila and M. tuberculosis enoyl reductases and provide genetic evidence consistent with the hypothesis that GFZ blocks growth of these bacteria by inhibiting their enoyl reductases. These findings, coupled with our inability to select a highly GFZ-resistant strain of L. pneumophila, the sensitivity to GFZ of all 22 drug-resistant M. tuberculosis strains tested, the emerging threat of extensively drug-resistant M. tuberculosis (51), and the paucity of new chemical entities for the treatment of tuberculosis, have prompted us to describe GFZ''s antibiotic activities. 相似文献
992.
Oliver Waidmann Thomas Pleli Karel Dvorak Christina Baehr Ulrich Mondorf Guido Plotz Ricardo M. Biondi Stefan Zeuzem Albrecht Piiper 《The Journal of biological chemistry》2009,284(47):32256-32263
Cyclic AMP analogs containing hydrophobic modification of C8 at the adenine ring such as 8-(4-chlorophenylthio)-cAMP (8-pCPT-cAMP) and 8-(4-chlorophenylthio)-2′-O-methyl-cAMP (8-pCPT-2′-O-methyl-cAMP) can penetrate membranes due to their high lipophilicity and directly activate intracellular cAMP effectors. Therefore, these cAMP analogs have been used in numerous studies, assuming that their effects reflect the consequences of direct activation of cAMP effectors. The present study provides evidence that 8-pCPT-modified cAMP analogs and their corresponding putative hydrolysis products (8-(4-chlorophenylthio)-adenosine (8-pCPT-ado) and 8-(4-chlorophenylthio)-2′-O-methyl-adenosine (8-pCPT-2′-O-methyl-ado)) inhibit the equilibrative nucleoside transporter 1 (ENT1). In PC12 cells, in which nucleoside transport strongly depended on ENT1, 8-pCPT-ado, 8-pCPT-2′-O-methyl-ado, and, to a smaller extent, 8-pCPT-2′-O-methyl-cAMP caused an increase of protein kinase A substrate motif phosphorylation and anti-apoptotic effect by an A2A adenosine receptor (A2AR)-dependent mechanism. In contrast, the effects of 8-pCPT-cAMP were mainly A2AR-independent. In HEK 293 showing little endogenous ENT1-dependent nucleoside transport, transfection of ENT1 conferred A2AR-dependent increase in protein kinase A substrate motif phosphorylation. Together, the data of the present study indicate that inhibition of ENT1 and activation of adenosine receptors have to be considered when interpreting the effects of 8-pCPT-substituted cAMP/adenosine analogs. 相似文献
993.
994.
Chester Bittencourt Sacramento Vanessa Dionisio Cantagalli Mariana Grings Leonardo Pinto Carvalho José Carlos Costa Baptista‐Silva Abram Beutel Cassia Toledo Bergamaschi Ruy Ribeiro de Campos Junior Jane Zveiter de Moraes Christina Maeda Takiya Vívian Yochiko Samoto Radovan Borojevic Flavia Helena da Silva Nance Beyer Nardi Hans Fernando Dohmann Hamilton Silva Junior Valderez Bastos Valero Sang Won Han 《The journal of gene medicine》2009,11(4):345-353
995.
996.
ABSTRACT John McCain, once considered a "friend" of Vietnam because of his support for normalized relations with the United States, has since lost his standing. Claims to inhumane treatment and torture while a prisoner in the "Hanoi Hilton" have met with angry denials and calls for more attention to the humanitarian care that McCain and others received. Recent U.S. allegations of human rights abuses in Vietnam following the Abu Ghraib prison scandal have further strained relations, as have charges leveled against Vietnamese small-scale producers of dishonest trade practices. Drawing on these exchanges, I examine competing representations of Vietnamese wartime acts that have permeated the "normalization" process. Neoliberal rhetorics aimed at "saving" the Vietnamese economy and its allegedly blemished human rights record are countered by discourses and images that lay claim to a Vietnamese "tradition" of wartime compassion and humanitarianism that also demands U.S. historical accountability for imperial violence and its aftermaths. [Keywords: neoliberalism, violence, human rights, Vietnam, historical memory] 相似文献
997.
Dong-Chuan Guo Christina L. Papke Van Tran-Fadulu Nili Avidan Dong H. Kim Marcia C. Willing Reed E. Pyeritz Ronald L. Dalman Ali J. Marian Eric A. Boerwinkle Lorraine Q. Frazier Joseph S. Coselli Anthony L. Estrera Sudha Veeraraghavan David A. Wheeler Robert K. Yu Steven E. Scherer L. Maximilian Buja 《American journal of human genetics》2009,84(5):617-627
The vascular smooth muscle cell (SMC)-specific isoform of α-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases. 相似文献
998.
Rudall PJ Remizowa MV Prenner G Prychid CJ Tuckett RE Sokoloff DD 《American journal of botany》2009,96(1):67-82
Reproductive units (RUs) of Trithuria, the sole genus of the early-divergent angiosperm family Hydatellaceae, are compared with flowers of their close relatives in Cabombaceae (Nymphaeales). Trithuria RUs combine features of flowers and inflorescences. They differ from typical flowers in possessing an "inside-out" morphology, with carpels surrounding stamens; furthermore, carpels develop centrifugally, in contrast to centripetal or simultaneous development in typical flowers. Trithuria RUs could be interpreted as pseudanthia of two or more cymose partial inflorescences enclosed within an involucre, but the bractlike involucral phyllomes do not subtend partial inflorescences and hence collectively resemble a typical perianth. Teratological forms of T. submersa indicate a tendency to fasciation and demonstrate that the inside-out structure-the primary feature that separates RUs of Hydatellaceae from more orthodox angiosperm flowers-can be at least partially modified, thus producing a morphology that is closer to an orthodox flower. The Trithuria RU could be described as a "nonflower", i.e., a structure that contains typical angiosperm carpels and stamens but does not allow recognition of a typical angiosperm flower. The term nonflower could combine cases of secondary loss of flower identity and cases of a prefloral condition, similar to those that gave rise to the angiosperm flower. Nonhomology among some angiosperm flowers could be due to iterative shifts between nonfloral construction and flower/inflorescence organization of reproductive organs. Potential testing of these hypotheses using evolutionary-developmental genetics is explored using preliminary data from immunolocalization of the floral meristem identity gene LEAFY in T. submersa, which indicated protein expression at different hierarchical levels. 相似文献
999.
Dohnal AM Graffi S Witt V Eichstill C Wagner D Ul-Haq S Wimmer D Felzmann T 《Journal of cellular and molecular medicine》2009,13(1):125-135
Manufacturing procedures for cellular therapies are continuously improved with particular emphasis on product safety. We previously developed a dendritic cell (DC) cancer vaccine technology platform that uses clinical grade lipopolysaccharide (LPS) and interferon (IFN)-y for the maturation of monocyte derived DCs. DCs are frozen after 6 hrs exposure at a semi-mature stage (smDCs) retaining the capacity to secret interleukin (IL)-12 and thus support cytolytic T-cell responses, which is lost at full maturation. We compared closed systems for monocyte enrichment from leucocyte apheresis products from healthy individuals using plastic adherence, CD14 selection, or CD2/19 depletion with magnetic beads, or counter flow centrifugation (elutriation) using a clinical grade in comparison to a research grade culture medium for the following DC generation. We found that elutriation was superior compared to the other methods showing 36 ± 4% recovery, which was approximately 5-fold higher as the most frequently used adherence protocol (8 ± 1%), and a very good purity (92 ± 5%) of smDCs. Immune phenotype and IL-12 secretion (adherence: 1.4 ± 0.4; selection: 20 ± 0.6; depletion: 1 ±0.5; elutriation: 3.6 ± 1.5 ng/ml) as well as the potency of all DCs to stimulate T cells in an allogeneic mixed leucocyte reaction did not show statistically significant differences. Research grade and clinical grade DC culture media were equally potent and freezing did not impair the functions of smDCs. Finally, we assessed the functional capacity of DC cancer vaccines manufactured for three patients using this optimized procedure thereby demonstrating the feasibility of manufacturing DC cancer vaccines that secret IL-12 (9.4 ± 6.4 ng/ml). We conclude that significant steps were taken here towards clinical grade DC cancer vaccine manufacturing. 相似文献
1000.
Srilakshmi M Sharma Dongseok Choi Stephen R Planck Christina A Harrington Carrie R Austin Jinnell A Lewis Tessa N Diebel Tammy M Martin Justine R Smith James T Rosenbaum 《Arthritis research & therapy》2009,11(6):R168-9