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31.
Members of all four families of ectonucleotidases, namely ectonucleoside triphosphate diphosphohydrolases (NTPDases), ectonucleotide
pyrophosphatase/phosphodiesterases (NPPs), ecto-5′-nucleotidase and alkaline phosphatases, have been identified in the renal
vasculature and/or tubular structures. In rats and mice, NTPDase1, which hydrolyses ATP through to AMP, is prominent throughout
most of the renal vasculature and is also present in the thin ascending limb of Henle and medullary collecting duct. NTPDase2
and NTPDase3, which both prefer ATP over ADP as a substrate, are found in most nephron segments beyond the proximal tubule.
NPPs catalyse not only the hydrolysis of ATP and ADP, but also of diadenosine polyphosphates. NPP1 has been identified in
proximal and distal tubules of the mouse, while NPP3 is expressed in the rat glomerulus and pars recta, but not in more distal
segments. Ecto-5′-nucleotidase, which catalyses the conversion of AMP to adenosine, is found in apical membranes of rat proximal
convoluted tubule and intercalated cells of the distal nephron, as well as in the peritubular space. Finally, an alkaline
phosphatase, which can theoretically catalyse the entire hydrolysis chain from nucleoside triphosphate to nucleoside, has
been identified in apical membranes of rat proximal tubules; however, this enzyme exhibits relatively high K
m values for adenine nucleotides. Although information on renal ectonucleotidases is still incomplete, the enzymes’ varied
distribution in the vasculature and along the nephron suggests that they can profoundly influence purinoceptor activity through
the hydrolysis, and generation, of agonists of the various purinoceptor subtypes. This review provides an update on renal
ectonucleotidases and speculates on the functional significance of these enzymes in terms of glomerular and tubular physiology
and pathophysiology. 相似文献
32.
Anitha Moorthy Amita Gupta Ramesh Bhosale Srikanth Tripathy Jayagowri Sastry Smita Kulkarni Madhuri Thakar Renu Bharadwaj Anju Kagal Arvind V. Bhore Sandesh Patil Vandana Kulkarni Varadharajan Venkataramani Usha Balasubramaniam Nishi Suryavanshi Carrie Ziemniak Nikhil Gupte Robert Bollinger Deborah Persaud for the India SWEN Study Team 《PloS one》2009,4(1)
Background
Daily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the “six-week extended-dose nevirapine” (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life.Methods/Findings
Standard population sequencing and cloning for viral subpopulations present at ≥5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant''s blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission.Conclusions/Significance
Use of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis.Trial Registration
ClinicalTrials.gov NCT00061321相似文献33.
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35.
Amreesh Parvez Samir Giri Renu Bisht Priti Saxena 《Indian journal of microbiology》2018,58(3):268-277
Type III polyketide synthases (PKSs) biosynthesize varied classes of metabolites with diverse bio-functionalities. Inherent promiscuous substrate specificity, multiple elongations of reaction intermediates and several modes of ring-closure, confer the proteins with the ability to generate unique scaffolds from limited substrate pools. Structural studies have identified crucial amino acid residues that dictate type III PKS functioning, though cyclization specific residues need further investigation. PKSIIINc, a functionally and structurally characterized type III PKS from the fungus, Neurospora crassa, is known to biosynthesize alkyl-resorcinol, alkyl-triketide- and alkyl-tetraketide-α-pyrone products. In this study, we attempted to identify residue positions governing cyclization specificity in PKSIIINc through comparative structural analysis. Structural comparisons with other type III PKSs revealed a motif with conserved hydroxyl/thiol groups that could dictate PKSIIINc catalysis. Site-directed mutagenesis of Cys120 and Ser186 to Ser and Cys, respectively, altered product profiles of mutant proteins. While both C120S and S186C proteins retained wild-type PKSIIINc product activity, S186C favoured lactonization and yielded higher amounts of the α-pyrone products. Notably, C120S gained new cyclization capability and biosynthesized acyl-phloroglucinol in addition to wild-type PKSIIINc products. Generation of alkyl-resorcinol and acyl-phloroglucinol by a single protein is a unique observation in fungal type III PKS family. Mutation of Cys120 to bulky Phe side-chain abrogated formation of tetraketide products and adversely affected overall protein stability as revealed by molecular dynamics simulation studies. Our investigations identify residue positions governing cyclization programming in PKSIIINc protein and provide insights on how subtle variations in protein cores dictate product profiles in type III PKS family. 相似文献
36.
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38.
We have demonstrated that the expressions of small molecular weight G-protein, H-Ras, and its effector protein, Raf-1, are
increased in the retina in diabetes, and the specific inhibitors of Ras function inhibit glucose-induced apoptosis of retinal
capillary cells. This study is to examine the contributory roles for H-Ras in glucose-induced apoptosis of retinal endothelial
cells by genetic manipulation of functionally active H-Ras levels. Bovine retinal endothelial cells were transfected with
the plasmids of either wild type (WT), constitutively active (V12) or dominant-negative (N17) H-Ras. Glucose-induced increase
in apoptosis, nitric oxide (NO) levels and activation of NF-κB and caspase-3 were determined in these genetically manipulated
cells. Exposure of bovine retinal endothelial cells to 20 mM glucose significantly increased H-Ras activation as determined
by Raf-1 binding assay. Overexpression of V12 in the endothelial cells further increased their glucose-induced apoptosis by
40%, NO levels by about 50%, and activated NF-κB and caspase-3 by about 30–40% compared to the untransfected cells incubated
in 20 mM glucose. In contrast, overexpression of the inactive mutant, N17, inhibited glucose-mediated increases in apoptotic
cell death, NO levels and NF-κB and caspase-3 activation; the values were significantly different (p < 0.02) compared to those obtained from the untransfected cells incubated under similar conditions. Our findings demonstrate
that H-Ras activation is important in the activation of the specific signaling events leading to the accelerated retinal capillary
cell apoptosis in hyperglycemic conditions, suggesting the possible use of H-Ras inhibitors to inhibit the pathogenesis of
diabetic retinopathy. 相似文献
39.
Removal of reproductive 'sink,' i.e., spikelets from wheat, after anthesis delays the rate of flag leaf senescence. Oxidative stress and the oxidative damage to proteins were studied in relation to nitrogen mobilization in wheat plants showing normal and delayed senescence. Wheat plants lacking a reproductive sink showed decreased oxidative stress, lower lipid peroxidation and maintained higher protein, oxidatively damaged proteins, and nitrogen levels as compared to plants with reproductive sink during monocarpic senescence. Oxidative damage to the proteins when not followed by high proteolytic activities led to a slower nitrogen mobilization in wheat plants lacking a reproductive sink. Thus, the influence of the reproductive sink was due to its ability to drive forward the nitrogen mobilization process through high ROS levels which mediated both damage to the proteins and influenced proteolytic activities. 相似文献
40.
Garg R Juncadella IJ Ramamoorthi N Ashish Ananthanarayanan SK Thomas V Rincón M Krueger JK Fikrig E Yengo CM Anguita J 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(10):6579-6583
Salp15 is an Ixodes scapularis salivary protein that inhibits CD4+ T cell activation through the repression of TCR ligation-triggered calcium fluxes and IL-2 production. We show in this study that Salp15 binds specifically to the CD4 coreceptor on mammalian host T cells. Salp15 specifically associates through its C-terminal residues with the outermost two extracellular domains of CD4. Upon binding to CD4, Salp15 inhibits the subsequent TCR ligation-induced T cell signaling at the earliest steps including tyrosine phosphorylation of the Src kinase Lck, downstream effector proteins, and lipid raft reorganization. These results provide a molecular basis to understanding the immunosuppressive activity of Salp15 and its specificity for CD4+ T cells. 相似文献