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81.
V. Guru KrishnaKumar Lokesh Baweja Krittika Ralhan Sharad Gupta 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(12):2590-2604
Background
Carbamylation is a non-enzymatic post-translational modification (PTM), which involves the covalent modification of N-terminus of protein or ε-amino group of Lys. The role of carbamylation in several age-related disorders is well documented, however, the relationship between carbamylation and neurodegenerative disorders including Alzheimer's disease remains uncharted.Methods
In the present study, using aggregation-prone tau-core hexapeptide fragments 306VQIVYK311 (PHF6) and 275VQIINK280 (PHF6*) as models, we have elucidated the effect of carbamylation on aggregation kinetics and the changes occurring in the 3-dimensional architecture of fibrils using biophysical assays and molecular dynamics simulations.Results
We found that carbamylation aids in amyloid formation and can convert the unstructured off-pathway aggregates into robust amyloids, which were toxic to cells. Electron microscopy images and molecular dynamics simulations of PHF6 fibrils showed that carbamylated peptides can form excess hydrogen bonds and modulate the pitch length and twist of peptides fibrils. We have also compared N-terminal carbamylation to acetylation and further extended our finding to full length tau that exhibits aggregation upon carbamylation even in the absence of any external inducer.Conclusion
Our in vitro and in silico results together suggest that carbamylation can modulate the aggregation pathway of the amyloidegenic sequences and cause structural changes in fibril assemblies.General significance
Carbamylation acts as a switch, which triggers the aggregation in short amyloidogenic peptide fragments and modulate the structural changes in resulting amyloid fibrils. 相似文献82.
Esraa Haj Yelena Losev V. Guru KrishnaKumar Edward Pichinuk Hamutal Engel Avi Raveh Ehud Gazit Daniel Segal 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(7):1565-1575
Background
Alzheimer's disease (AD) is the most common neurodegenerative disorder which is characterized by the deposits of intra-cellular tau protein and extra-cellular amyloid-β (Aβ) peptides in the human brain. Understanding the mechanism of protein aggregation and finding compounds that are capable of inhibiting its aggregation is considered to be highly important for disease therapy.Methods
We used an in vitro High-Throughput Screening for the identification of potent inhibitors of tau aggregation using a proxy model; a highly aggregation-prone hexapeptide fragment 306VQIVYK311 derived from tau. Using ThS fluorescence assay we screened a library of 2401 FDA approved, bio-active and natural compounds in attempt to find molecules which can efficiently modulate tau aggregation.Results
Among the screened compounds, palmatine chloride (PC) alkaloid was able to dramatically reduce the aggregation propensity of PHF6 at sub-molar concentrations. PC was also able to disassemble preformed aggregates of PHF6 and reduce the amyloid content in a dose-dependent manner. Insights obtained from MD simulation showed that PC interacted with the key residues of PHF6 responsible for β-sheet formation, which could likely be the mechanism of inhibition and disassembly. Furthermore, PC could effectively inhibit the aggregation of full-length tau and disassemble preformed aggregates.Conclusions
We found that PC possesses “dual functionality” towards PHF6 and full-length tau, i.e. inhibit their aggregation and disassemble pre-formed fibrils.General significance
The “dual functionality” of PC is valuable as a disease modifying strategy for AD, and other tauopathies, by inhibiting their progress and reducing the effect of fibrils already present in the brain. 相似文献83.
S Bhatnagar V Nigam P Y Guru J C Katiyar A Mukherjee R C Gupta S Batra M Seth A P Bhaduri 《Indian journal of experimental biology》1992,30(7):619-623
Impact of change of heteroatom in pentavalent heterocycles, viz., pyrroles, isoxazoles, imidazoles and crotonates on the profile of antileishmanial activity against amastigotes of L. donovani using in vivo test system and macrophage-amastigote culture system has been studied. Sixty-three compounds were tested. Nine imidazoles showed marginal activity in vivo, whereas 3 out of 10 compounds of isoxazolone series and 2 out of 4 substituted aminocrotonates exhibited antileishmanial activity. Of the 30 substituted pyrroles, except 8 all showed antileishmanial activity in vivo on day 7 post treatment. 相似文献
84.
Experiments were carried out to establish the role of glutathione reductase (GR), if any, in the metabolic conversion of disulfiram (DS) to diethyldithiocarbamate (DDC). It was observed that, under standard assay conditions, whereas DS was incorporated as a substrate instead of oxidised glutathione (GSSG), the enzymes from both human liver extract and yeast sources failed to reduce the parent compound, implying that glutathione reductase perse do not reduce disulfiram. However, the incorporation of disulfiram into an assay system comprising of GSSG, NADPH and reductase resulted in DS reduction to DDC. Further, the observation, that the GR assay system devoid of either GSSG or NADPH was found to lack DS reducing ability, implies that GSH as a reaction product of GR system is responsible for the reduction of DS to DDC. The results of in-vitro experiments indicated that GSH perse could reduce DS to DDC nonenzymatically, with a stoichiometric relationship of 2:1. Thus it is inferred that GR perse do not reduce DS, whereas GSH, as an intermediary metabolite of GR system, brings about non-enzymatic reduction of DS via a sulfhydral group exchange reaction. 相似文献
85.
A 2.8-Mb Clone Contig of the Multiple Endocrine Neoplasia Type 1 (MEN1) Region at 11q13 总被引:1,自引:0,他引:1
Siradanahalli C. Guru Shodimu-Emmanuel Olufemi Pachiappan Manickam Christiano Cummings Linn M. Gieser Brian L. Pike Michael L. Bittner Yuan Jiang A.Craig Chinault Norma J. Nowak Anna Brzozowska Judy S. Crabtree Yingping Wang Bruce A. Roe Jane M. Weisemann Mark S. Boguski Sunita K. Agarwal A.Lee Burns Allen M. Spiegel Stephen J. Marx Wendy L. Flejter Pieter J. de Jong Francis S. Collins Settara C. Chandrasekharappa 《Genomics》1997,42(3):436
86.
Hina Mir Neeraj Kapur Rajesh Singh Guru Sonpavde James W. Lillard Jr. 《Cell cycle (Georgetown, Tex.)》2016,15(6):819-826
Despite state of the art cancer diagnostics and therapies offered in clinic, prostate cancer (PCa) remains the second leading cause of cancer-related deaths. Hence, more robust therapeutic/preventive regimes are required to combat this lethal disease. In the current study, we have tested the efficacy of Andrographolide (AG), a bioactive diterpenoid isolated from Andrographis paniculata, against PCa. This natural agent selectively affects PCa cell viability in a dose and time-dependent manner, without affecting primary prostate epithelial cells. Furthermore, AG showed differential effect on cell cycle phases in LNCaP, C4-2b and PC3 cells compared to retinoblastoma protein (RB?/?) and CDKN2A lacking DU-145 cells. G2/M transition was blocked in LNCaP, C4-2b and PC3 after AG treatment whereas DU-145 cells failed to transit G1/S phase. This difference was primarily due to differential activation of cell cycle regulators in these cell lines. Levels of cyclin A2 after AG treatment increased in all PCa cells line. Cyclin B1 levels increased in LNCaP and PC3, decreased in C4-2b and showed no difference in DU-145 cells after AG treatment. AG decreased cyclin E2 levels only in PC3 and DU-145 cells. It also altered Rb, H3, Wee1 and CDC2 phosphorylation in PCa cells. Intriguingly, AG reduced cell viability and the ability of PCa cells to migrate via modulating CXCL11 and CXCR3 and CXCR7 expression. The significant impact of AG on cellular and molecular processes involved in PCa progression suggests its potential use as a therapeutic and/or preventive agent for PCa. 相似文献
87.
88.
Kailash N Pandey Huong T Nguyen Guru Dutt Sharma Shang-Jin Shi Alison M Kriegel 《The Journal of biological chemistry》2002,277(7):4618-4627
We examined the kinetics of internalization, trafficking, and down-regulation of recombinant guanylyl cyclase/natriuretic peptide receptor-A (NPRA) utilizing stably transfected 293 cells expressing a very high density of receptors. After atrial natriuretic peptide (ANP) binding to NPRA, ligand-receptor complexes are internalized, processed intracellularly, and sequestered into subcellular compartments, which provided an approach to examining directly the dynamics of metabolic turnover of NPRA in intact cells. The translocation of ligand-receptor complexes from cell surface to intracellular compartments seems to be linked to ANP-dependent down-regulation of NPRA. Using tryptic proteolysis of cell surface receptors, it was found that approximately 40-50% of internalized ligand-receptor complexes recycled back to the plasma membrane with an apparent t(12) = 8 min. The recycling of NPRA was blocked by the lysosomotropic agent chloroquine, the energy depleter dinitrophenol, and also by low temperature, suggesting that recycling of the receptor is an energy- and temperature-dependent process. Data suggest that approximately 70-80% of internalized (125)I-ANP is processed through a lysosomal degradative pathway; however, 20-25% of internalized ligand is released intact into the cell exterior through an alternative mechanism involving an chloroquine-insensitive pathway. It is implied that internalization and processing of bound ANP-NPRA complexes may play an important role in mediating the biological action of hormone and the receptor protein. In retrospect, this could occur at the level of receptor regulation or through the initiation of ANP mediated signals. It is envisioned that the endocytotic pathway of ligand-receptor complexes of ANP-NPRA would lead to termination and/or diminished responsiveness of ANP in target cells. 相似文献
89.
In four genotypes of chickpea (Cicer arietinum L.) BG 362, BG 372, BG 329 and C235 the relationship between somatic embryogenesis
of leaf explants and ethylene and methane evolution was studied. In BG 362, which was more embryogenic than other genotypes,
a higher ethylene:methane ratio of 5.8:1 at day one after inoculation in the induction medium and a lower ethylene:methane
ratio of 2.89:1 in the maturation medium was found. On the contrary, in BG 372 with the least embryogenic potential, a lower
ethylene:methane ratio of 1.7:1 in the induction medium and a higher ethylene:methane ratio of 4:1 in the maturation medium
was found. Thus, these ratios in induction and maturation stages seems to be markers for embryogenesis in leaf explants of
chickpea.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
90.