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Bhattacharjee PS Huq TS Mandal TK Graves RA Muniruzzaman S Clement C McFerrin HE Hill JM 《PloS one》2011,6(1):e15905
Angiogenesis is a hallmark of tumor development and metastasis and now a validated target for cancer treatment. We previously reported that a novel dimer peptide (apoEdp) derived from the receptor binding region of human apolipoprotein E (apoE) inhibits virus-induced angiogenesis. However, its role in tumor anti-angiogenesis is unknown. This study demonstrates that apoEdp has anti-angiogenic property in vivo through reduction of tumor growth in a mouse model and ocular angiogenesis in a rabbit eye model. Our in vitro studies show that apoEdp inhibits human umbilical vein endothelial cell proliferation, migration, invasion and capillary tube formation. We document that apoEdp inhibits vascular endothelial growth factor-induced Flk-1 activation as well as downstream signaling pathways that involve c-Src, Akt, eNOS, FAK, and ERK1/2. These in vitro data suggest potential sites of the apoE dipeptide inhibition that could occur in vivo.This is the first evidence that a synthetic dimer peptide mimicking human apoE has anti-angiogenesis functions and could be an anti-tumor drug candidate. 相似文献
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Matthew J. Cooper Nathan J. Cox Eric I. Zimmerman Brian J. Dewar James S. Duncan Martin C. Whittle Thien A. Nguyen Lauren S. Jones Sreerupa Ghose Roy David M. Smalley Pei Fen Kuan Kristy L. Richards Richard I. Christopherson Jian Jin Stephen V. Frye Gary L. Johnson Albert S. Baldwin Lee M. Graves 《PloS one》2013,8(6)
Protein kinases play key roles in oncogenic signaling and are a major focus in the development of targeted cancer therapies. Imatinib, a BCR-Abl tyrosine kinase inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML). However, resistance to imatinib may be acquired by BCR-Abl mutations or hyperactivation of Src family kinases such as Lyn. We have used multiplexed kinase inhibitor beads (MIBs) and quantitative mass spectrometry (MS) to compare kinase expression and activity in an imatinib-resistant (MYL-R) and -sensitive (MYL) cell model of CML. Using MIB/MS, expression and activity changes of over 150 kinases were quantitatively measured from various protein kinase families. Statistical analysis of experimental replicates assigned significance to 35 of these kinases, referred to as the MYL-R kinome profile. MIB/MS and immunoblotting confirmed the over-expression and activation of Lyn in MYL-R cells and identified additional kinases with increased (MEK, ERK, IKKα, PKCβ, NEK9) or decreased (Abl, Kit, JNK, ATM, Yes) abundance or activity. Inhibiting Lyn with dasatinib or by shRNA-mediated knockdown reduced the phosphorylation of MEK and IKKα. Because MYL-R cells showed elevated NF-κB signaling relative to MYL cells, as demonstrated by increased IκBα and IL-6 mRNA expression, we tested the effects of an IKK inhibitor (BAY 65-1942). MIB/MS and immunoblotting revealed that BAY 65-1942 increased MEK/ERK signaling and that this increase was prevented by co-treatment with a MEK inhibitor (AZD6244). Furthermore, the combined inhibition of MEK and IKKα resulted in reduced IL-6 mRNA expression, synergistic loss of cell viability and increased apoptosis. Thus, MIB/MS analysis identified MEK and IKKα as important downstream targets of Lyn, suggesting that co-targeting these kinases may provide a unique strategy to inhibit Lyn-dependent imatinib-resistant CML. These results demonstrate the utility of MIB/MS as a tool to identify dysregulated kinases and to interrogate kinome dynamics as cells respond to targeted kinase inhibition. 相似文献
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Tarun Arya Chandan Kishor Venkateshwarlu Saddanapu Ravikumar Reddi Anthony Addlagatta 《PloS one》2013,8(10)
Protein N-terminal methionine excision is an essential co-translational process that occurs in the cytoplasm of all organisms. About 60-70% of the newly synthesized proteins undergo this modification. Enzyme responsible for the removal of initiator methionine is methionine aminopeptidase (MetAP), which is a dinuclear metalloprotease. This protein is conserved through all forms of life from bacteria to human except viruses. MetAP is classified into two isoforms, Type I and II. Removal of the map gene or chemical inhibition is lethal to bacteria and to human cell lines, suggesting that MetAP could be a good drug target. In the present study we describe the discovery of a new genetic variant of the Type I MetAP that is present predominantly in the streptococci bacteria. There are two inserts (insert one: 27 amino acids and insert two: four residues) within the catalytic domain. Possible glycosylation and phosphorylation posttranslational modification sites are identified in the ‘insert one’. Biochemical characterization suggests that this enzyme behaves similar to other MetAPs in terms of substrate specificity. Crystal structure Type Ia MetAP from Streptococcus pneumoniae (SpMetAP1a) revealed that it contains two molecules in the asymmetric unit and well ordered inserts with structural features that corroborate the possible posttranslational modification. Both the new inserts found in the SpMetAP1a structurally align with the P-X-X-P motif found in the M. tuberculosis and human Type I MetAPs as well as the 60 amino acid insert in the human Type II enzyme suggesting possible common function. In addition, one of the β-hairpins within in the catalytic domain undergoes a flip placing a residue which is essential for enzyme activity away from the active site and the β-hairpin loop of this secondary structure in the active site obstructing substrate binding. This is the first example of a MetAP crystallizing in the inactive form. 相似文献
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Rajan Kumar Pandey Drista Sharma Tarun Kumar Bhatt Shyam Sundar 《Journal of biomolecular structure & dynamics》2013,31(12):2541-2553
Visceral leishmaniasis (VL) affects Indian subcontinent, African and South American continent, and it covers 70 countries worldwide. Visceral form of leishmaniasis is caused by Leishmania donovani in Indian subcontinent which is lethal if left untreated. Extensive resistance to antileishmanial drugs such as sodium stibogluconate, pentamidine and miltefosine and their decreased efficacy has been reported in the endemic region. Amphotericin B drug has shown good antileishmanial activity with significant toxicity, but its cost of treatment has limited the outreach of this treatment to affected people living in endemic zone. So, there is an urgent need to identify new antileishmanial drugs with excellent activity and minimal toxicity issues. Trypanothione reductase, a component of antioxidant system, is necessary for parasite growth and survival to raise infection. To develop potential inhibitor, we docked nine hundred and eighty-four 5-nitroimidazole analogues along with clomipramine which is a well-known inhibitor for TR. Total one hundred and forty-seven 5-nitroimidazole analogues with better docking score than clomipramine were chosen for ADMET and QikProp studies. Among these imidazole analogues, total twenty-four imidazole analogues and clomipramine were chosen on the basis of their ADMET, QikProp, and prime MM-GBSA study. Later on, two analogues with best MM-GBSA dG bind were undergone molecular dynamic simulation to ensure protein–ligand interactions. Using above approach, we confirm that ethyl 2-acetyl-5-[4-butyl-2-(3-hydroxypentyl)-5-nitro-1H-imidazol-1-yl]pent-2-enoate can be a drug candidate against L. donovani for the treatment of VL in the Indian subcontinent. 相似文献
17.
Craveur Pierrick Narwani Tarun J. Rebehmed Joseph de Brevern Alexandre G. 《Amino acids》2019,51(7):1065-1079
Amino Acids - Post-translational modifications (PTMs) are known to play a critical role in the regulation of protein functions. Their impact on protein structures and their link to disorder regions... 相似文献
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The ratio of gelatin to sodium carboxymethyl cellulose (SCMC) at which maximum yield was obtained was optimized. This optimized
ratio of gelatin to SCMC along with other parameters was used to prepare microparticles of different sizes. Vegetable oil
was used as emulsion medium. Effect of various factors like amount of surfactant, concentration of polymer on the formation,
and size of the microparticles was investigated. These microparticles were used as carrier for isoniazid. Among different
cross-linkers, glutaraldehyde was found to be the most effective cross-linker at the temperature and pH at which the reaction
was carried out. The loading efficiency and release behavior of loaded microparticles were found to be dependent on the amount
of cross-linker used, concentration of drug, and time of immersion. Maximum drug loading efficiency was observed at higher
immersion time. The release rate of isoniazid was more at higher pH compared to that of at lower pH. The sizes of the microparticles
were investigated by scanning electron microscope. In all the cases, the microparticles formed were found spherical in shape
except to those at low stirring speed where they were agglomerated. Fourier transform infrared study indicated the successful
incorporation of isoniazid into the microparticles. Differential scanning calorimetry study showed a molecular level dispersion
of isoniazid in the microparticles. X-ray diffraction study revealed the development of some crystallinity due to the encapsulation
of isoniazid. 相似文献
20.
The arbuscular mycorrhizal status of fifteen mangroves and one mangrove associate was investigated from 27 sites of three
inundation types namely, diurnal, usual springtide and summer springtide. Roots and rhizospheric soil samples were analysed
for spore density, frequency of mycorrhizal colonization and some chemical characteristics of soil. Relative abundance, frequency
and spore richness of AMF were assessed at each inundation type. All the plant species except Avicennia alba exhibited mycorrhizal colonization. The study demonstrated that mycorrhizal colonization and spore density were more influenced
by host plant species than tidal inundation. Forty four AMF species belonging to six genera, namely Acaulospora, Entrophospora, Gigaspora, Glomus, Sclerocystis and Scutellospora, were recorded. Glomus mosseae exhibited highest frequency at all the inundation types; Glomus fistulosum, Sclerocystis coremioides and Glomus mosseae showed highest relative abundance at sites inundated by usual springtides, summer springtides and diurnal tides, respectively.
Spore richness of AMF was of the order usual springtide > diurnal > summer springtide inundated sites. The mean spore richness
was 3.27. Diurnally inundated sites had the lowest concentrations of salinity, available phosphorus, exchangeable potassium,
sodium and magnesium. Statistical analyses indicated that mycorrhizal frequency and AMF spore richness were significantly
negatively correlated to soil salinity. Spore richness was also significantly negatively correlated to available phosphorus.
The soil parameters of the usual springtide inundated sites appeared to be favourable for the existence of maximum number
of AMF. Glomus mosseae was the predominant species in terms of frequency in the soils of the Sundarbans. 相似文献