排序方式: 共有183条查询结果,搜索用时 31 毫秒
71.
Giorgio Giannattasio Ying Lai Francescopaolo Granata Carine M. Mounier Laxman Nallan Rob Oslund Christina C. Leslie Gianni Marone Gérard Lambeau Michael H. Gelb Massimo Triggiani 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2009,1791(2):92-102
Macrophages are a major source of lipid mediators in the human lung. Expression and contribution of cytosolic (cPLA2) and secreted phospholipases A2 (sPLA2) to the generation of lipid mediators in human macrophages are unclear. We investigated the expression and role of different PLA2s in the production of lipid mediators in primary human lung macrophages. Macrophages express the alpha, but not the zeta isoform of group IV and group VIA cPLA2 (iPLA2). Two structurally-divergent inhibitors of group IV cPLA2 completely block arachidonic acid release by macrophages in response to non-physiological (Ca2+ ionophores and phorbol esters) and physiological agonists (lipopolysaccharide and Mycobacterium protein derivative). These inhibitors also reduce by 70% the synthesis of platelet-activating factor by activated macrophages. Among the full set of human sPLA2s, macrophages express group IIA, IID, IIE, IIF, V, X and XIIA, but not group IB and III enzymes. Me-Indoxam, a potent and cell impermeable inhibitor of several sPLA2s, has no effect on arachidonate release or platelet-activating factor production. Agonist-induced exocytosis is not influenced by cPLA2 inhibitors at concentrations that block arachidonic acid release. Our results indicate that human macrophages express cPLA2-alpha, iPLA2 and several sPLA2s. Cytosolic PLA2-alpha is the major enzyme responsible for lipid mediator production in human macrophages. 相似文献
72.
Ervin D. Nagy Ye Chu Yufang Guo Sameer Khanal Shunxue Tang Yan Li Weibo B. Dong Patricia Timper Christopher Taylor Peggy Ozias-Akins C. Corley Holbrook Vadim Beilinson Niels C. Nielsen H. Thomas Stalker Steven J. Knapp 《Molecular breeding : new strategies in plant improvement》2010,26(2):357-370
Rma, a dominant root-knot nematode resistance gene introduced into tetraploid peanut (Arachis hypogaea) from a synthetic allotetraploid donor (TxAG-6), has been widely deployed in modern cultivars. The genomic location and borders of the alien chromosome segment introgressed from TxAG-6 into NemaTAM (a BC7-derived introgression line) and other modern cultivars carrying Rma have not been genetically mapped, and resistance gene candidates (RGCs) have not been identified for Rma. Our study focused on densely populating the alien introgression with codominant DNA markers, identifying and mapping the borders of the alien introgression carried by NemaTAM, and identifying RGCs for Rma. Altogether, 2,847 simple sequence repeat (SSR) and 380 single strand conformational polymorphism (SSCP) markers were screened for linkage to Rma-247 of the SSCP markers targeted 202 nucleotide binding site (NBS) leucine-rich repeat (LRR) and other resistance (R) gene homologs (75 were identified by mining a peanut EST database). SSR, NBS-LRR, and Ser/Thr receptor-like protein loci within the alien introgression co-segregated with Rma in an F4 population (Gregory × Tifguard) and were tightly linked and spanned 3.4 cM in an F5 population (NemaTAM × GP-NC-WS-14). By comparative mapping in the A-genome progenitor of peanut (A. duranensis), Rma was discovered to have been introduced on an interstitial alien chromosome segment spanning one-third to one-half of chromosome 9A. Numerous codominant DNA markers were identified for finer mapping of Rma, shortening the alien introgression harboring Rma by marker-assisted selection, and introducing novel root-knot nematode R-genes into peanut by targeting syntenic segments on chromosomes 9A and 9B in wild diploid donors. 相似文献
73.
Morita H Khanal S Rastogi S Suzuki G Imai M Todor A Sharov VG Goldstein S O'Neill TP Sabbah HN 《American journal of physiology. Heart and circulatory physiology》2006,290(6):H2522-H2527
Matrix metalloproteinases (MMPs) contribute to the progression of left ventricular (LV) dysfunction and remodeling associated with heart failure (HF). The present study examined the long-term effects of a selective MMP inhibitor PG-530742 (PG) on the progression of LV dysfunction and remodeling in dogs with HF. Chronic HF [LV ejection fraction (LVEF), =36%] was produced by multiple sequential intracoronary microembolizations in 24 dogs. Two weeks after the last embolization, dogs were randomized to 3 mo of therapy with either high-dose (HD) PG (3.5 mg/kg, n = 8), low-dose (LD) PG (0.2 mg/kg, n = 8), or to a matched placebo (PL, n = 8). PG has been shown to produce complete inhibition of MMP-2, -3, -9, and -13, while sparing MMPs-1 and -7. Hemodynamic and echocardiographic measurements were made before and 3 mo after initiating therapy. In PL and LD dogs, LVEF decreased significantly, and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased significantly during the 3-mo follow-up period. Whereas in HD dogs ejection fraction increased from 36 +/- 1 to 40 +/- 1% (P = 0.003), EDV and ESV decreased (59 +/- 4 vs. 57 +/- 4 ml, P = 0.02; and 38 +/- 2 vs. 34 +/- 2 ml, P = 0.00001, respectively). When compared with controls, HD-treated dogs showed 30% reduction in replacement fibrosis, 29% reduction in interstitial fibrosis, and 28% reduction in myocyte cross-sectional area. mRNA expression of selective MMPs was also reduced in LV tissue in HD- but not LD-treated dogs. In conclusion, in dogs with moderate HF, long-term monotherapy with HD selective MMP inhibitor PG prevents LV remodeling and the progression of global LV dysfunction. 相似文献
74.
New pyrrolobenzodiazepine (PBD) dimers have been developed that are composed of two DC-81 subunits tethered to their C8 positions through piperazine moiety side-armed with alkaneoxy linkers (composed of 2-5 carbons). DNA thermal denaturation studies show that after 18h of incubation with calf thymus DNA at a 1:5 ligand/DNA ratio, one of them, 6a, increases the DeltaT(m) value by 24.0 degrees C. Thus, incorporation of a piperazine moiety instead of an inert alkanedioxy linker alone significantly enhances the DNA binding ability, and the analogous dimer 4 that lacks a piperazine moiety in the linker spacer elevates melting by only 15.1 degrees C under identical experimental conditions. This illustrates the effect of introducing a piperazine ring in the middle of such an alkanedioxy linker which produces several hydrophobic interactions and could also achieve a superior isohelical fit within the DNA minor groove. Interestingly, these dimers 6a-d are significantly more cytotoxic than 4 in a number of human cancer cell lines, in particular, compound 6c is highly potent for almost all the nine human cancer cell lines. 相似文献
75.
Ilka Nemere Natalio Garbi Gunter J. H?mmerling Ramesh C. Khanal 《The Journal of biological chemistry》2010,285(41):31859-31866
We have crossed ERp57flx/flx mice with commercially available mice expressing villin-driven cre-recombinase. Lysates of intestinal epithelial cells were prepared from knock-out (KO) mice and littermates (LM) and used in Western blot analyses with Ab099 against the N terminus of the 1,25D3-MARRS (membrane-associated, rapid response steroid-binding) receptor: LM mice exhibited one positive band, which was absent in preparations from KO mice. Saturation analyses of cell lysates with [3H]1,25D3 revealed negligible binding in preparations from either female or male KOs. Lysates from female and male LM mice had similar affinities but different numbers of binding sites. Isolated enterocytes were tested for steroid-stimulated calcium uptake. Treatment of cells from female or male LM mice with 1,25D3 elicited enhanced calcium uptake in females and males within 5 min. Intestinal cells from KO mice exhibited a severely blunted or completely absent response to hormone. Confocal microscopy of intestinal cells revealed the presence of cell surface vitamin D receptors. However, antibodies to the vitamin D receptor failed to block 1,25D3-stimulated calcium uptake. In chick enterocytes we have found that the PKA pathway mediates calcium uptake. The time course for activation of PKA in mouse enterocytes paralleled that for enhanced calcium uptake and for LM females reached 250% of controls within 5 min, and 150% of controls in cells prepared from LM males. Enterocytes from female or male KO mice failed to exhibit steroid hormone-stimulated PKA activity, but did respond to forskolin with enhanced calcium uptake. We conclude that the 1,25D3-MARRS receptor is of central importance to steroid hormone-stimulated calcium uptake in mammalian intestinal cells. 相似文献
76.
An efficient and consistent method of monoclonal antibody (mAb) purification can improve process productivity and product consistency. Although protein A chromatography removes most host‐cell proteins (HCPs), mAb aggregates and the remaining HCPs are challenging to remove in a typical bind‐and‐elute cation‐exchange chromatography (CEX) polishing step. A variant of the bind‐and‐elute mode is the displacement mode, which allows strongly binding impurities to be preferentially retained and significantly improves resin utilization. Improved resin utilization renders displacement chromatography particularly suitable in continuous chromatography operations. In this study we demonstrate and exploit sample displacement between a mAb and impurities present at low prevalence (0.002%–1.4%) using different multicolumn designs and recycling. Aggregate displacement depends on the residence time, sample concentration, and solution environment, the latter by enhancing the differences between the binding affinities of the product and the impurities. Displacement among the mAb and low‐prevalence HCPs resulted in an effectively bimodal‐like distribution of HCPs along the length of a multi‐column system, with the mAb separating the relatively more basic group of HCPs from those that are more acidic. Our findings demonstrate that displacement of low‐prevalence impurities along multiple CEX columns allows for selective separation of mAb aggregates and HCPs that persist through protein A chromatography. 相似文献
77.
Perroud Pierre-François Demko Viktor Ako Ako Eugene Khanal Rajendra Bokor Boris Pavlovič Andrej Jásik Ján Johansen Wenche 《Plant molecular biology》2021,107(4-5):307-325
Plant Molecular Biology - In Physcomitrium patens, PpRH1/PpRH2 are GUCT-domain-containing DEAD-BOX RNA helicases localize to the nucleus. They are implicated in cell and tissue development in all... 相似文献
78.
Andris Jankevics Bart Cuypers Ilse Maes Sandip Mukherjee Basudha Khanal Suman Rijal Syamal Roy Fred Opperdoes Rainer Breitling Jean‐Claude Dujardin 《Molecular microbiology》2013,90(2):428-442
Antimonial (sodium stibogluconate, SSG) resistance and differentiation have been shown to be closely linked in Leishmania donovani, with SSG‐resistant strains showing an increased capacity to generate infectious (metacyclic) forms. This is the first untargeted LC‐MS metabolomics study which integrated both phenomena in one experimental design and provided insights into metabolic differences between three clinical L. donovani strains with a similar genetic background but different SSG‐susceptibilities. We performed this analysis at different stages during promastigote growth and in the absence or presence of drug pressure. When comparing SSG‐resistant and SSG‐sensitive strains, a number of metabolic changes appeared to be constitutively present in all growth stages, pointing towards a clear link with SSG‐resistance, whereas most metabolic changes were only detected in the stationary stage. These changes reflect the close intertwinement between SSG‐resistance and an increased metacyclogenesis in resistant parasites. The metabolic changes suggest that SSG‐resistant parasites have (i) an increased capacity for protection against oxidative stress; (ii) a higher fluidity of the plasma membrane; and (iii) a metabolic survival kit to better endure infection. These changes were even more pronounced in a resistant strain kept under SbIII drug pressure. 相似文献
79.
Rajendra P. Tanpure Clinton S. George Tracy E. Strecker Laxman Devkota Justin K. Tidmore Chen-Ming Lin Christine A. Herdman Matthew T. MacDonough Madhavi Sriram David J. Chaplin Mary Lynn Trawick Kevin G. Pinney 《Bioorganic & medicinal chemistry》2013,21(24):8019-8032
Diversely functionalized, fused aryl–alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7]annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds. In order to extend the structure–activity relationship (SAR) knowledge base related to benzosuberene anti-cancer agents, a series of eleven analogues (including KGP18) were prepared in which the methoxylation pattern on the pendant aryl ring as well as functional group incorporation on the fused aryl ring were varied. The synthetic approach to these compounds featured a sequential Wittig olefination, reduction, Eaton’s reagent-mediated cyclization strategy to achieve the core benzosuberone intermediate, and represented a higher-yielding synthesis of KGP18 (which we prepared previously through a ring-expansion strategy). Incorporation of a fluorine or chlorine atom at the 1-position of the fused aryl ring or replacement of one of the methoxy groups with hydrogen (on the pendant aryl ring of KGP18) led to benzosuberene analogues that were both strongly inhibitory against tubulin assembly (IC50 approximately 1.0 μM) and strongly cytotoxic against selected human cancer cell lines (for example, GI50 = 5.47 nM against NCI-H460 cells with fluoro-benzosuberene analogue 37). A water-soluble phosphate prodrug salt of KGP18 (referred to as KGP265, compound 44) and a water-soluble serinamide salt (compound 48) of KGP156 were also synthesized and evaluated in this study. 相似文献
80.
Epco Hasker Paritosh Malaviya Kamlesh Gidwani Albert Picado Bart Ostyn Sangeeta Kansal Rudra Pratap Singh Om Prakash Singh Ankita Chourasia Abhishek Kumar Singh Ravi Shankar Mary E. Wilson Basudha Khanal Suman Rijal Marleen Boelaert Shyam Sundar 《PLoS neglected tropical diseases》2014,8(1)