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101.
102.
Lupachyk S Shevalye H Maksimchyk Y Drel VR Obrosova IG 《Free radical biology & medicine》2011,50(10):1400-1409
This study evaluated the role of poly(ADP-ribose) polymerase (PARP) in systemic oxidative stress and 4-hydoxynonenal adduct accumulation in diabetic peripheral neuropathy. Control and streptozotocin-diabetic rats were maintained with or without treatment with the PARP inhibitor, 1,5-isoquinolinediol, 3 mg kg(-1) day(-1), for 10 weeks after an initial 2 weeks. Treatment efficacy was evaluated by poly(ADP-ribosyl)ated protein content in peripheral nerve and spinal cord (Western blot analysis) and dorsal root ganglion neurons and nonneuronal cells (fluorescence immunohistochemistry), as well as by indices of peripheral nerve function. Diabetic rats displayed increased urinary isoprostane and 8-hydroxy-2'-deoxyguanosine excretion (ELISA) and 4-hydroxynonenal adduct accumulation in endothelial and Schwann cells of the peripheral nerve, neurons, astrocytes, and oligodendrocytes of the spinal cord and neurons and glial cells of the dorsal root ganglia (double-label fluorescence immunohistochemistry), as well as motor and sensory nerve conduction velocity deficits, thermal hypoalgesia, and tactile allodynia. PARP inhibition counteracted diabetes-induced systemic oxidative stress and 4-hydroxynonenal adduct accumulation in peripheral nerve and spinal cord (Western blot analysis) and dorsal root ganglion neurons (perikarya, fluorescence immunohistochemistry), which correlated with improvement of large and small nerve fiber function. The findings reveal the important role of PARP activation in systemic oxidative stress and 4-hydroxynonenal adduct accumulation in diabetic peripheral neuropathy. 相似文献
103.
Oleg V. Stroganov Fedor N. Novikov Alexey A. Zeifman Viktor S. Stroylov Ghermes G. Chilov 《Proteins》2011,79(9):2693-2710
A new graph–theoretical approach called thermodynamic sampling of amino acid residues (TSAR) has been elaborated to explicitly account for the protein side chain flexibility in modeling conformation‐dependent protein properties. In TSAR, a protein is viewed as a graph whose nodes correspond to structurally independent groups and whose edges connect the interacting groups. Each node has its set of states describing conformation and ionization of the group, and each edge is assigned an array of pairwise interaction potentials between the adjacent groups. By treating the obtained graph as a belief‐network—a well‐established mathematical abstraction—the partition function of each node is found. In the current work we used TSAR to calculate partition functions of the ionized forms of protein residues. A simplified version of a semi‐empirical molecular mechanical scoring function, borrowed from our Lead Finder docking software, was used for energy calculations. The accuracy of the resulting model was validated on a set of 486 experimentally determined pKa values of protein residues. The average correlation coefficient (R) between calculated and experimental pKa values was 0.80, ranging from 0.95 (for Tyr) to 0.61 (for Lys). It appeared that the hydrogen bond interactions and the exhaustiveness of side chain sampling made the most significant contribution to the accuracy of pKa calculations. Proteins 2011; © 2011 Wiley‐Liss, Inc. 相似文献
104.
Kouyos RD von Wyl V Hinkley T Petropoulos CJ Haddad M Whitcomb JM Böni J Yerly S Cellerai C Klimkait T Günthard HF Bonhoeffer S;Swiss HIV Cohort Study 《PLoS pathogens》2011,7(11):e1002321
HIV-1 replicative capacity (RC) provides a measure of within-host fitness and is determined in the context of phenotypic drug resistance testing. However it is unclear how these in-vitro measurements relate to in-vivo processes. Here we assess RCs in a clinical setting by combining a previously published machine-learning tool, which predicts RC values from partial pol sequences with genotypic and clinical data from the Swiss HIV Cohort Study. The machine-learning tool is based on a training set consisting of 65000 RC measurements paired with their corresponding partial pol sequences. We find that predicted RC values (pRCs) correlate significantly with the virus load measured in 2073 infected but drug na?ve individuals. Furthermore, we find that, for 53 pairs of sequences, each pair sampled in the same infected individual, the pRC was significantly higher for the sequence sampled later in the infection and that the increase in pRC was also significantly correlated with the increase in plasma viral load and with the length of the time-interval between the sampling points. These findings indicate that selection within a patient favors the evolution of higher replicative capacities and that these in-vitro fitness measures are indicative of in-vivo HIV virus load. 相似文献
105.
Viktor Brovkovych Yongkang Zhang Svitlana Brovkovych Richard D. Minshall Randal A. Skidgel 《Journal of cellular and molecular medicine》2011,15(2):258-269
Inducible nitric oxide synthase (iNOS) is a major source of nitric oxide during inflammation whose activity is thought to be controlled primarily at the expression level. The B1 kinin receptor (B1R) post‐translationally activates iNOS beyond its basal activity via extracellular signal regulated kinase (ERK)‐mediated phosphorylation of Ser745. Here we identified the signalling pathway causing iNOS activation in cytokine‐treated endothelial cells or HEK293 cells transfected with iNOS and B1R. To allow kinetic measurements of nitric oxide release, we used a sensitive porphyrinic microsensor (response time = 10 msec.; 1 nM detection limit). B1Rs signalled through Gαi coupling as ERK and iNOS activation were inhibited by pertussis toxin. Furthermore, transfection of constitutively active mutant Gαi Q204L but not Gαq Q209L resulted in high basal iNOS‐derived nitric oxide. G‐βγ subunits were also necessary as transfection with the β‐adrenergic receptor kinase C‐terminus inhibited the response. B1R‐dependent iNOS activation was also inhibited by Src family kinase inhibitor PP2 and trans‐fection with dominant negative Src. Other ERK‐MAP kinase members were involved as the response was inhibited by dominant negative H‐Ras, Raf kinase inhibitor, ERK activation inhibitor and MEK inhibitor PD98059. In contrast, PI3 kinase inhibitor LY94002, calcium chelator 1,2‐bis‐(o‐Aminophenoxy)‐ethane‐N,N,N′,N′‐tetraacetic acid, tetraacetoxymethyl ester (BAPTA‐AM), protein kinase C inhibitor calphostin C and protein kinase C activator PMA had no effect. Angiotensin converting enzyme inhibitor enalaprilat also directly activated B1Rs to generate high output nitric oxide via the same pathway. These studies reveal a new mechanism for generating receptor‐regulated high output nitric oxide in inflamed endothelium that may play an important role in the development of vascular inflammation. 相似文献
106.
107.
Kotzsch M Dorn J Doetzer K Schmalfeldt B Krol J Baretton G Kiechle M Schmitt M Magdolen V 《Biological chemistry》2011,392(11):1047-1051
High tumor tissue mRNA expression of the tumor biological factors uPAR, uPAR-del4/5, or rab31 is associated with shorter distant metastasis-free and overall survival in breast cancer patients. To evaluate whether these factors are also clinically relevant in ovarian cancer, we quantified the respective mRNA levels in primary tumor tissue of advanced ovarian cancer patients (n=103) and evaluated their association with clinicopathological parameters and patients' prognosis. mRNA expression levels of all three markers did not show any significant association with overall or progression-free survival, demonstrating that these factors have no prognostic value in advanced ovarian cancer. 相似文献
108.
The Mss4 (mammalian suppressor of yeast Sec4) is an evolutionarily highly conserved protein and is expressed in all mammalian tissues. Although its precise biological function is still elusive, it has been shown to associate with a subset of secretory Rab proteins (Rab1b, Rab3a, Rab8a, Rab10) and to possess a rather low guanine nucleotide exchange factor (GEF) activity towards them in vitro (Rab1, Rab3a and Rab8a). By screening a human placenta cDNA library with Mss4 as bait, we identified several Rab GTPases (Rab12, Rab13 and Rab18) as novel Mss4-binding Rab proteins. Only exocytic but no endocytic Rab GTPases were found in our search. The binding of Mss4 to Rab proteins was confirmed by direct yeast two-hybrid interaction, by co-immunoprecipitation from lysates of mammalian cells, by immunofluorescence colocalisation as well as by direct in vitro binding studies. Analysis of Mss4 catalytic activity towards different Rab substrates confirmed that it is a somewhat inefficient GEF. These data, together with our mutational analysis of Mss4-Rab binding capacity, support the already proposed idea that Mss4 functions rather as a chaperone for exocytic Rab GTPases than as a GEF. 相似文献
109.
110.
von Oheimb PV Albrecht C Riedel F Du L Yang J Aldridge DC Bössneck U Zhang H Wilke T 《PloS one》2011,6(10):e26307