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61.
Marisa J. Stachowski Ronald J. Holewinski Eric Grote Vidya Venkatraman Jennifer E. Van Eyk Jonathan A. Kirk 《Proteomics》2018,18(19)
Cardiac dyssynchrony arises from conduction abnormalities during heart failure and worsens morbidity and mortality. Cardiac resynchronization therapy (CRT) re‐coordinates contraction using bi‐ventricular pacing, but the cellular and molecular mechanisms involved remain largely unknown. The aim is to determine how dyssynchronous heart failure (HFdys) alters the phospho‐proteome and how CRT interacts with this unique phospho‐proteome by analyzing Ser/Thr and Tyr phosphorylation. Phospho‐enriched myocardium from dog models of Control, HFdys, and CRT is analyzed via MS. There were 209 regulated phospho‐sites among 1761 identified sites. Compared to Con and CRT, HFdys is hyper‐phosphorylated and tyrosine phosphorylation is more likely to be involved in signaling that increased with HFdys and was exacerbated by CRT. For each regulated site, the most‐likely targeting‐kinase is predicted, and CK2 is highly specific for sites that are “fixed” by CRT, suggesting activation of CK2 signaling occurs in HFdys that is reversed by CRT, which is supported by western blot analysis. These data elucidate signaling networks and kinases that may be involved and deserve further study. Importantly, a possible role for CK2 modulation in CRT has been identified. This may be harnessed in the future therapeutically to compliment CRT, improving its clinical effects. 相似文献
62.
Taylor (1953) proposed a distance function in connection with the logit χ2 estimator. For product (associated) multinomial distributions, he showed that minimization of the distance function yields BAN estimators. Aithal (1986) and Rao (1989) considered a modified version of Taylor's distance function and showed that a member belonging to this class leads to a second order efficient estimator. In this paper we consider Taylor's distance function and show that a member belonging to this class produces a second order efficient estimator. In addition to the above two, the m.l. estimator is also second order efficient. In order to compare these three second order efficient estimators, the small sample variances of the estimators are estimated through a simulation study. The results indicate that the variance of the m.l. estimator is the smallest in most of the cases. 相似文献
63.
Nagarajan Muthukaman Macchindra Tambe Mahamadhanif Shaikh Dnyandeo Pisal Sanjay Deshmukh Shital Tondlekar Neelam Sarode Lakshminarayana Narayana Jitendra M. Gajera Vidya G. Kattige Srinivasa Honnegowda Vikas Karande Abhay Kulkarni Dayanidhi Behera Satyawan B. Jadhav Girish S. Gudi Neelima Khairatkar-Joshi Laxmikant A. Gharat 《Bioorganic & medicinal chemistry letters》2017,27(11):2594-2601
A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2 release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F = 33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model. 相似文献
64.
65.
Telomerase expression strongly correlates with the grade of malignancy in glioma with inhibition illustrating a definite increase
in chemosensitivity. This study was designed to investigate the effects of a green tea derivative, epigallocatechin-3-gallate
(EGCG); together with either cisplatin or tamoxifen in glioma, and to investigate whether these effects are mediated through
telomerase suppression. EGCG showed a significant cytotoxic effect on 1321N1 cells after 24 h and on U87-MG cells after 72 h
(P < 0.001) without significantly affecting the normal astrocytes. Treatment with EGCG inhibited telomerase expression significantly
(P < 0.01) and enhanced the effect of cisplatin and tamoxifen in both 1321N1 (P < 0.01) and U87-MG (P < 0.001) cells. EGCG, as a natural product has enormous potential to be an anti-cancer agent capable of enhancing tumour
cell sensitivity to therapy. 相似文献
66.
Manasi Alok Telang Prashant Pyati Mohini Sainani Vidya Shrikant Gupta Ashok Prabhakar Giri 《Insect Science》2009,16(5):371-380
Abstract Bitter gourd ( Momordica charantia L.) seeds contain several squash-type serine proteinase inhibitors (PIs), which inhibit the digestive proteinases of the polyphagous insect pest Helicoverpa armigera . In the present work isolation of a DNA sequence encoding the mature peptide of a trypsin inhibitor McTI-II, its cloning and expression as a recombinant protein using Pichia pastoris have been reported. Recombinant McTI-II inhibited bovine trypsin at 1: 1 molar ratio, as expected, but did not inhibit chymotrypsin or elastase. McTI-II also strongly inhibited trypsin-like proteinases (81% inhibition) as well as the total proteolytic activity of digestive proteinases (70% inhibition) from the midgut of H. armigera larvae. The insect larvae fed with McTI-II-incorporated artificial diet suffered over 70% reduction in the average larval weight after 12 days of feeding. Moreover, ingestion of McTI-II resulted in 23% mortality in the larval population. The strong antimetabolic activity of McTI-II toward H. armigera indicates its probable use in developing insect tolerance in susceptible plants. 相似文献
67.
Daniel Rittirsch Michael A. Flierl Danielle E. Day Brian A. Nadeau Firas S. Zetoune J. Vidya Sarma Clement M. Werner Guido A. Wanner Hans-Peter Simmen Markus S. Huber-Lang Peter A. Ward 《PLoS pathogens》2009,5(6)
Pathogen-pattern-recognition by Toll-like receptors (TLRs) and pathogen clearance after immune complex formation via engagement with Fc receptors (FcRs) represent central mechanisms that trigger the immune and inflammatory responses. In the present study, a linkage between TLR4 and FcγR was evaluated in vitro and in vivo. Most strikingly, in vitro activation of phagocytes by IgG immune complexes (IgGIC) resulted in an association of TLR4 with FcγRIII (CD16) based on co-immunoprecipitation analyses. Neutrophils and macrophages from TLR4 mutant (mut) mice were unresponsive to either lipopolysaccharide (LPS) or IgGIC in vitro, as determined by cytokine production. This phenomenon was accompanied by the inability to phosphorylate tyrosine residues within immunoreceptor tyrosine-based activation motifs (ITAMs) of the FcRγ-subunit. To transfer these findings in vivo, two different models of acute lung injury (ALI) induced by intratracheal administration of either LPS or IgGIC were employed. As expected, LPS-induced ALI was abolished in TLR4 mut and TLR4−/− mice. Unexpectedly, TLR4 mut and TLR4−/− mice were also resistant to development of ALI following IgGIC deposition in the lungs. In conclusion, our findings suggest that TLR4 and FcγRIII pathways are structurally and functionally connected at the receptor level and that TLR4 is indispensable for FcγRIII signaling via FcRγ-subunit activation. 相似文献
68.
In vitro and in vivo assessment of herb drug interactions 总被引:3,自引:0,他引:3
Herbal products contain several chemicals that are metabolized by phase 1 and phase 2 pathways and also serve as substrates for certain transporters. Due to their interaction with these enzymes and transporters there is a potential for alteration in the activity of drug metabolizing enzymes and transporters in presence of herbal components. Induction and inhibition of drug metabolizing enzymes and transporters by herbal component has been documented in several in vitro studies. While these studies offer a system to determine the potential for a herbal component to alter the pharmacokinetics of a drug, they cannot always be used to predict the magnitude of any potential effect in vivo. In vivo studies are the ultimate way to determine the clinical importance of herb drug interactions. However, lack of content uniformity and lack of documentation of the bioavailability of herbal components makes even in vivo human studies difficult to interpret as the effect may be product specific. It appears that St. John's wort extract is probably one of the most important herbal product that increases the metabolism and decreases the efficacy of several drugs. Milk thistle on the other hand appears to have minimal effect on phase 1 pathways and limited data exists for phase 2 pathways and transporter activity in vivo. Further systematic studies are necessary to assess the significance of herb drug interactions. 相似文献
69.
Plant litter chemistry alters the content and composition of organic carbon associated with soil mineral and aggregate fractions in invaded ecosystems 总被引:1,自引:0,他引:1 下载免费PDF全文
Vidya Suseela Myrna Simpson Brian Powell Nishanth Tharayil 《Global Change Biology》2017,23(10):4002-4018
Through the input of disproportionate quantities of chemically distinct litter, invasive plants may potentially influence the fate of organic matter associated with soil mineral and aggregate fractions in some of the ecosystems they invade. Although context dependent, these native ecosystems subjected to prolonged invasion by exotic plants may be instrumental in distinguishing the role of plant–microbe–mineral interactions from the broader edaphic and climatic influences on the formation of soil organic matter (SOM). We hypothesized that the soils subjected to prolonged invasion by an exotic plant that input recalcitrant litter (Japanese knotweed, Polygonum cuspidatum) would have a greater proportion of plant‐derived carbon (C) in the aggregate fractions, as compared with that in adjacent soil inhabited by native vegetation that input labile litter, whereas the soils under an invader that input labile litter (kudzu, Pueraria lobata) would have a greater proportion of microbial‐derived C in the silt‐clay fraction, as compared with that in adjacent soils that receive recalcitrant litter. At the knotweed site, the higher C content in soils under P. cuspidatum, compared with noninvaded soils inhabited by grasses and forbs, was limited to the macroaggregate fraction, which was abundant in plant biomarkers. The noninvaded soils at this site had a higher abundance of lignins in mineral and microaggregate fractions and suberin in the macroaggregate fraction, partly because of the greater root density of the native species, which might have had an overriding influence on the chemistry of the above‐ground litter input. At the kudzu site, soils under P. lobata had lower C content across all size fractions at a 0–5 cm soil depth despite receiving similar amounts of Pinus litter. Contrary to our prediction, the noninvaded soils receiving recalcitrant Pinus litter had a similar abundance of plant biomarkers across both mineral and aggregate fractions, potentially because of the higher surface area of soil minerals at this site. The plant biomarkers were lower in the aggregate fractions of the P. lobata‐invaded soils, compared with noninvaded pine stands, potentially suggesting a microbial co‐metabolism of pine‐derived compounds. These results highlight the complex interactions among litter chemistry, soil biota, and minerals in mediating soil C storage in unmanaged ecosystems; these interactions are particularly important under global changes that may alter plant species composition and hence the quantity and chemistry of litter inputs in terrestrial ecosystems. 相似文献
70.
Integrated gut/liver microphysiological systems elucidates inflammatory inter‐tissue crosstalk 下载免费PDF全文
Wen L.K. Chen Collin Edington Emily Suter Jiajie Yu Jeremy J. Velazquez Jason G. Velazquez Michael Shockley Emma M. Large Raman Venkataramanan David J. Hughes Cynthia L. Stokes David L. Trumper Rebecca L. Carrier Murat Cirit Linda G. Griffith Douglas A. Lauffenburger 《Biotechnology and bioengineering》2017,114(11):2648-2659
A capability for analyzing complex cellular communication among tissues is important in drug discovery and development, and in vitro technologies for doing so are required for human applications. A prominent instance is communication between the gut and the liver, whereby perturbations of one tissue can influence behavior of the other. Here, we present a study on human gut‐liver tissue interactions under normal and inflammatory contexts, via an integrative multi‐organ platform comprising human liver (hepatocytes and Kupffer cells), and intestinal (enterocytes, goblet cells, and dendritic cells) models. Our results demonstrated long‐term (>2 weeks) maintenance of intestinal (e.g., barrier integrity) and hepatic (e.g., albumin) functions in baseline interaction. Gene expression data comparing liver in interaction with gut, versus isolation, revealed modulation of bile acid metabolism. Intestinal FGF19 secretion and associated inhibition of hepatic CYP7A1 expression provided evidence of physiologically relevant gut‐liver crosstalk. Moreover, significant non‐linear modulation of cytokine responses was observed under inflammatory gut‐liver interaction; for example, production of CXCR3 ligands (CXCL9,10,11) was synergistically enhanced. RNA‐seq analysis revealed significant upregulation of IFNα/β/γ signaling during inflammatory gut‐liver crosstalk, with these pathways implicated in the synergistic CXCR3 chemokine production. Exacerbated inflammatory response in gut‐liver interaction also negatively affected tissue‐specific functions (e.g., liver metabolism). These findings illustrate how an integrated multi‐tissue platform can generate insights useful for understanding complex pathophysiological processes such as inflammatory organ crosstalk. Biotechnol. Bioeng. 2017;114: 2648–2659. © 2017 Wiley Periodicals, Inc. 相似文献