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111.
Lalitha Ramachandran Kanjoormana Aryan Manu Muthu K. Shanmugam Feng Li Kodappully Sivaraman Siveen Shireen Vali Shweta Kapoor Taher Abbasi Rohit Surana Duane T. Smoot Hassan Ashktorab Patrick Tan Kwang Seok Ahn Chun Wei Yap Alan Prem Kumar Gautam Sethi 《The Journal of biological chemistry》2012,287(45):38028-38040
Gastric cancer (GC) is a lethal malignancy and the second most common cause of cancer-related deaths. Although treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of isorhamnetin (IH), a 3′-O-methylated metabolite of quercetin on the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of PPAR-γ inhibitor. We found that IH increased PPAR-γ activity and modulated the expression of PPAR-γ regulated genes in GC cells. Also, the increase in PPAR-γ activity was reversed in the presence of PPAR-γ-specific inhibitor and a mutated PPAR-γ dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-γ. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity and could competitively bind to PPAR-γ. IH significantly increased the expression of PPAR-γ in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the PPAR-γ activation pathway in GC. 相似文献
112.
113.
Yang J Wu J Steichen JM Kornev AP Deal MS Li S Sankaran B Woods VL Taylor SS 《Journal of molecular biology》2012,415(4):666-679
Eukaryotic protein kinases (EPKs) feature two coevolved structural segments, the Activation segment, which starts with the Asp-Phe-Gly (DFG) and ends with the Ala-Pro-Glu (APE) motifs, and the helical GHI subdomain that comprises αG-αH-αI helices. Eukaryotic-like kinases have a much shorter Activation segment and lack the GHI subdomain. They thus lack the conserved salt bridge interaction between the APE Glu and an Arg from the GHI subdomain, a hallmark signature of EPKs. Although the conservation of this salt bridge in EPKs is well known and its implication in diseases has been illustrated by polymorphism analysis, its function has not been carefully studied. In this work, we use murine cAMP-dependent protein kinase (protein kinase A) as the model enzyme (Glu208 and Arg280) to examine the role of these two residues. We showed that Ala replacement of either residue caused a 40- to 120-fold decrease in catalytic efficiency of the enzyme due to an increase in K(m)(ATP) and a decrease in k(cat). Crystal structures, as well as solution studies, also demonstrate that this ion pair contributes to the hydrophobic network and stability of the enzyme. We show that mutation of either Glu or Arg to Ala renders both mutant proteins less effective substrates for upstream kinase phosphoinositide-dependent kinase 1. We propose that the Glu208-Arg280 pair serves as a center hub of connectivity between these two structurally conserved elements in EPKs. Mutations of either residue disrupt communication not only between the two segments but also within the rest of the molecule, leading to altered catalytic activity and enzyme regulation. 相似文献
114.
115.
Connelly L Jang H Arce FT Ramachandran S Kagan BL Nussinov R Lal R 《Biochemistry》2012,51(14):3031-3038
Alzheimer's disease (AD) is a misfolded protein disease characterized by the accumulation of β-amyloid (Aβ) peptide as senile plaques, progressive neurodegeneration, and memory loss. Recent evidence suggests that AD pathology is linked to the destabilization of cellular ionic homeostasis mediated by toxic pores made of Aβ peptides. Understanding the exact nature by which these pores conduct electrical and molecular signals could aid in identifying potential therapeutic targets for the prevention and treatment of AD. Here using atomic force microscopy (AFM) and molecular dynamics (MD) simulations, we compared the imaged pore structures with models to predict channel conformations as a function of amino acid sequence. Site-specific amino acid (AA) substitutions in the wild-type Aβ(1-42) peptide yield information regarding the location and significance of individual AA residues to its characteristic structure-activity relationship. We selected two AAs that our MD simulation predicted to inhibit or permit pore conductance. The substitution of Phe19 with Pro has previously been shown to eliminate conductance in the planar lipid bilayer system. Our MD simulations predict a channel-like shape with a collapsed pore, which is supported by the AFM channel images. We suggest that proline, a known β-sheet breaker, creates a kink in the center of the pore and prevents conductance via blockage. This residue may be a viable target for drug development studies aiming to inhibit Aβ from inducing ionic destabilization toxicity. The substitution of Phe20 with Cys exhibits pore structures indistinguishable from the wild type in AFM images. MD simulations predict site 20 to face the solvated pore. Overall, the mutations support the previously predicted β-sheet-based channel structure. 相似文献
116.
AG Bick J Flannick K Ito S Cheng RS Vasan MG Parfenov DS Herman SR Depalma N Gupta SB Gabriel BH Funke HL Rehm EJ Benjamin J Aragam HA Taylor ER Fox C Newton-Cheh S Kathiresan CJ O'Donnell JG Wilson DM Altshuler JN Hirschhorn JG Seidman C Seidman 《American journal of human genetics》2012,91(3):513-519
Rare sarcomere protein variants cause dominant hypertrophic and dilated cardiomyopathies. To evaluate whether allelic variants in eight sarcomere genes are associated with cardiac morphology and function in the community, we sequenced 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts. Out of the total, 11.2% of individuals had one or more rare nonsynonymous sarcomere variants. The prevalence of likely pathogenic sarcomere variants was 0.6%, twice the previous estimates; however, only four of the 22 individuals had clinical manifestations of hypertrophic cardiomyopathy. Rare sarcomere variants were associated with an increased risk for adverse cardiovascular events (hazard ratio: 2.3) in the FHS cohort, suggesting that cardiovascular risk assessment in the general population can benefit from rare variant analysis. 相似文献
117.
118.
Zhao Y Yu Y Zhai J Ramachandran V Dinh TT Meyers BC Mo B Chen X 《Current biology : CB》2012,22(8):689-694
MicroRNAs (miRNAs), small interfering RNAs (siRNAs), and piwi-interacting RNAs (piRNAs) impact numerous biological processes in eukaryotes. In addition to biogenesis, turnover contributes to the steady-state levels of small RNAs. One major factor that stabilizes miRNAs and siRNAs in plants as well as siRNAs and piRNAs in animals is 2'-O-methylation on the 3' terminal ribose by the methyltransferase HUA ENHANCER1 (HEN1) [1-6]. Genetic studies with Arabidopsis, Drosophila, and zebrafish hen1 mutants show that 2'-O-methylation protects small RNAs from 3'-to-5' truncation and 3' uridylation, the addition of nontemplated nucleotides, predominantly uridine [2, 7, 8]. Uridylation is a widespread phenomenon that is not restricted to small RNAs in hen1 mutants and is often associated with their reduced accumulation ([7, 9, 10]; reviewed in [11]). The enzymes responsible for 3' uridylation of small RNAs when they lack methylation in plants or animals have remained elusive. Here, we identify the Arabidopsis HEN1 SUPPRESSOR1 (HESO1) gene as responsible for small RNA uridylation in hen1 mutants. HESO1 exhibits terminal nucleotidyl transferase activity, prefers uridine as the substrate nucleotide, and is completely inhibited by 2'-O-methylation. We show that uridylation leads to miRNA degradation, and the degradation is most likely through an enzyme that is distinct from that causing the 3' truncation in hen1 mutants. 相似文献
119.
Jiang SY Bhalla R Ramamoorthy R Luan HF Venkatesh PN Cai M Ramachandran S 《Transgenic research》2012,21(4):785-795
Both drought and high salinity stresses are major abiotic factors that limit the yield of agricultural crops. Transgenic techniques have been regarded as effective ways to improve crops in their tolerance to these abiotic stresses. Functional characterization of genes is the prerequisite to identify candidates for such improvement. Here, we have investigated the biological functions of an Oryza sativa Ribosome-inactivating protein gene 18 (OSRIP18) by ectopically expressing this gene under the control of CaMV 35S promoter in the rice genome. We have generated 11 independent transgenic rice plants and all of them showed significantly increased tolerance to drought and high salinity stresses. Global gene expression changes by Microarray analysis showed that more than 100 probe sets were detected with up-regulated expression abundance while signals from only three probe sets were down-regulated after over-expression of OSRIP18. Most of them were not regulated by drought or high salinity stresses. Our data suggested that the increased tolerance to these abiotic stresses in transgenic plants might be due to up-regulation of some stress-dependent/independent genes and OSRIP18 may be potentially useful in further improving plant tolerance to various abiotic stresses by over-expression. 相似文献
120.
Ramachandran E Kalaivani P Prabhakaran R Rath NP Brinda S Poornima P Padma VV Natarajan K 《Metallomics : integrated biometal science》2012,4(2):218-227
New complexes, [Ni(HL)(PPh(3))]Cl (1), [Pd(L)(PPh(3))](2), and [Pd(L)(AsPh(3))](3), were synthesized from the reactions of 4-chloro-5-methyl-salicylaldehyde thiosemicarbazone [H(2)L] with [NiCl(2)(PPh(3))(2)], [PdCl(2)(PPh(3))(2)] and [PdCl(2)(AsPh(3))(2)]. They were characterized by IR, electronic, (1)H-NMR spectral data. Further, the structures of the complexes have been determined by single crystal X-ray diffraction. While the thiosemicarbazone coordinated as binegative tridentate (ONS) in complexes 2 and 3, it is coordinated as mono negative tridentate (ONS) in 1. The interactions of the new complexes with calf thymus DNA was examined by absorption and emission spectra, and viscosity measurements. Moreover, the antioxidant properties of the new complexes have also been tested against DPPH radical in which complex 1 exhibited better activity than that of the other two complexes 2 and 3. The in vitro cytotoxicity of complexes 1-3 against A549 and HepG2 cell lines was assayed, and the new complexes exhibited higher cytotoxic activity with lower IC(50) values indicating their efficiency in killing the cancer cells even at very low concentrations. 相似文献