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1.
Shubhra Majumder Mark Slabodnick Amanda Pike Joseph Marquardt Harold A. Fisk 《Cell cycle (Georgetown, Tex.)》2012,11(19):3666-3678
Centrioles are duplicated during S-phase to generate the two centrosomes that serve as mitotic spindle poles during mitosis. The centrosomal pool of the Mps1 kinase is important for centriole assembly, but how Mps1 is delivered to centrosomes is unknown. Here we have identified a centrosome localization domain within Mps1 and identified the mitochondrial porin VDAC3 as a protein that binds to this region of Mps1. Moreover, we show that VDAC3 is present at the mother centriole and modulates centriole assembly by recruiting Mps1 to centrosomes. 相似文献
2.
Chumanevich AA Causey CP Knuckley BA Jones JE Poudyal D Chumanevich AP Davis T Matesic LE Thompson PR Hofseth LJ 《American journal of physiology. Gastrointestinal and liver physiology》2011,300(6):G929-G938
Inflammatory bowel diseases (IBDs), mainly Crohn's disease and ulcerative colitis, are dynamic, chronic inflammatory conditions that are associated with an increased colon cancer risk. Inflammatory cell apoptosis is a key mechanism for regulating IBD. Peptidylarginine deiminases (PADs) catalyze the posttranslational conversion of peptidylarginine to peptidylcitrulline in a calcium-dependent, irreversible reaction and mediate the effects of proinflammatory cytokines. Because PAD levels are elevated in mouse and human colitis, we hypothesized that a novel small-molecule inhibitor of the PADs, i.e., chloramidine (Cl-amidine), could suppress colitis in a dextran sulfate sodium mouse model. Results are consistent with this hypothesis, as demonstrated by the finding that Cl-amidine treatment, both prophylactic and after the onset of disease, reduced the clinical signs and symptoms of colitis, without any indication of toxic side effects. Interestingly, Cl-amidine drives apoptosis of inflammatory cells in vitro and in vivo, providing a mechanism by which Cl-amidine suppresses colitis. In total, these data help validate the PADs as therapeutic targets for the treatment of IBD and further suggest Cl-amidine as a candidate therapy for this disease. 相似文献
3.
Deepak Poudyal Xiangli Cui Phuong Mai Le Anne B. Hofseth Anthony Windust Mitzi Nagarkatti Prakash S. Nagarkatti Aaron J. Schetter Curtis C. Harris Lorne J. Hofseth 《PloS one》2013,8(10)
Metastasis of colon cancer cells increases the risk of colon cancer mortality. We have recently shown that American ginseng prevents colon cancer, and a Hexane extract of American Ginseng (HAG) has particularly potent anti-inflammatory and anti-cancer properties. Dysregulated microRNA (miR) expression has been observed in several disease conditions including colon cancer. Using global miR expression profiling, we observed increased miR-29b in colon cancer cells following exposure to HAG. Since miR-29b plays a role in regulating the migration of cancer cells, we hypothesized that HAG induces miR-29b expression to target matrix metalloproteinase-2 (MMP-2) thereby suppressing the migration of colon cancer cells. Results are consistent with this hypothesis. Our study supports the understanding that targeting MMP-2 by miR-29b is a mechanism by which HAG suppresses the migration of colon cancer cells. 相似文献
4.
Xiangli Cui Erin E. Witalison Alena P. Chumanevich Alexander A. Chumanevich Deepak Poudyal Venkataraman Subramanian Aaron J. Schetter Curtis C. Harris Paul R. Thompson Lorne J. Hofseth 《PloS one》2013,8(1)
Protein Arginine Deiminases (PADs) catalyze the post-translational conversion of peptidyl-Arginine to peptidyl-Citrulline in a calcium-dependent, irreversible reaction. Evidence is emerging that PADs play a role in carcinogenesis. To determine the cancer-associated functional implications of PADs, we designed a small molecule PAD inhibitor (called Chor-amidine or Cl-amidine), and tested the impact of this drug on the cell cycle. Data derived from experiments in colon cancer cells indicate that Cl-amidine causes a G1 arrest, and that this was p53-dependent. In a separate set of experiments, we found that Cl-amidine caused a significant increase in microRNA-16 (miRNA-16), and that this increase was also p53-dependent. Because miRNA-16 is a putative tumor suppressor miRNA, and others have found that miRNA-16 suppresses proliferation, we hypothesized that the p53-dependent G1 arrest associated with PAD inhibition was, in turn, dependent on miRNA-16 expression. Results are consistent with this hypothesis. As well, we found the G1 arrest is at least in part due to the ability of Cl-amidine-mediated expression of miRNA-16 to suppress its'' G1-associated targets: cyclins D1, D2, D3, E1, and cdk6. Our study sheds light into the mechanisms by which PAD inhibition can protect against or treat colon cancer. 相似文献
5.
The complex between the proteins MDM2 and p53 is a promising drug target for cancer therapy. The residues 19-26 of p53 have been biochemically and structurally demonstrated to be a most critical region to maintain the association of MDM2 and p53. Variation of the amino acid sequence in this range obviously alters the binding affinity. Surprisingly, suitable substitutions contiguous to this region of the p53 peptides can yield tightly binding peptides. The peptide variants may differ by a single residue that vary little in their structural conformations and yet are characterized by large differences in their binding affinities. In this study a systematic analysis into the role of single C-terminal mutations of a 12 residue fragment of the p53 transactivation domain (TD) and an equivalent phage optimized peptide (12/1) were undertaken to elucidate their mechanistic and thermodynamic differences in interacting with the N-terminal of MDM2. The experimental results together with atomistically detailed dynamics simulations provide insight into the principles that govern peptide design protocols with regard to protein-protein interactions and peptidomimetic design. 相似文献
6.
Mycobacteriosis is a progressive disease of a wide range of wild and captive, marine and freshwater fish species. Conventional detection of fish Mycobacteria is based on histopathology, culture, and biochemical characteristics. The present study analyzed the occurrence of Mycobacteria in clinically ill ornamental fish of different species, from different places of India. In first group, 60 fish were examined for presence of granulomatous inflammation and acid-fast bacteria. Thirty-eight (63.34 %) fish were positive for granulomatous inflammations. Presences of acid-fast bacteria were detected in 27 (45 %) fish having granulomatous inflammation and in two (3.33 %) fish without granulomatous inflammation. In total, AFB were found in 29 (48.34 %) of the 60 fish examined. In second group, 20 fish having granulomatous inflammation, 12 (60 %) samples were positive using Ziehl–Neelsen (Z-N) staining and 11 (55 %) of them were culture positive. Eight (40 %) samples were Z-N negative but two (10 %) of them were culture positive. In total, 13 (65 %) of the 20 examined fish were culture positive. On the basis of biochemical tests and 16S rRNA sequencing, 13 isolates were identified: five as Mycobacterium fortuitum, five as Mycobacterium gordonae, and three as Mycobacterium chelonae. In comparison of two decontamination methods, 2 % HCl treatment was better than 4 % NaOH treatment. Mycobacteria recovery from decontaminated samples was significantly high on Lowenstein–Jensen medium compared to Middlebrook 7H11 agar and Stonebrink (SB) media. The disease is transmissible from fish to fish and also from fish to human, so the significance of Mycobacteria in ornamental fish should not be overlooked. 相似文献
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8.
Christopher J. Brown Shubhra Ghosh Dastidar David W. Coomber Chandra Verma 《Journal of molecular biology》2010,395(4):871-4416
Peptide aptamers are simple structures, often made up of a single-variable peptide loop constrained within a constant scaffold protein. Aptamers were rationally designed by inserting peptides into a solvent-exposed loop on thioredoxin (Trx). They were designed to interact with the proteins elongation initiation factor 4E (eIF4E) and mouse double minute 2 (MDM2) and were then validated by competitive fluorescence anisotropy experiments. The constructed aptamers interacted with eIF4E and MDM2 with apparent Kd values of 1.25 ± 0.06 μM and 0.09 ± 0.01 μM, respectively, as determined by isothermal titration calorimetry (ITC). The MDM2 aptamer (SuperTIP) interacted ∼ 2-fold more tightly with MDM2 than the free linear peptide (12.1 peptide), while the eIF4E aptamer elongation initiation factor 4GI-SG interacted ∼ 5-fold less strongly than the free linear peptide (elongation initiation factor 4GI). These differences in binding with respect to each aptamer's free peptide reveal that there are more factors involved than just constraining a peptide in a scaffold that lead to tighter binding. ITC studies of aptamer interactions reveal an enthalpic component more favorable than that for the free linear peptides, as well as a larger unfavorable entropic component. These results indicated that stapling of the free peptide in the scaffold increases the favorable enthalpy of the interaction with the target protein. Thermostability studies also revealed that peptide insertion significantly destabilized the Trx scaffold by ∼ 27 °C. It is this destabilization that leads to an increase in the flexibility of the Trx scaffold, which presumably is lost upon the aptamer's interaction with the target protein and is the cause of the increase in unfavorable entropy in the ITC studies. The precise origin of the enthalpic effect was further studied using molecular dynamics for the MDM2-SuperTIP system, which revealed that there were also favorable electrostatic interactions between the Trx scaffold and the MDM2 protein itself, as well as with the inserted peptide. This work reveals that any increase in the binding affinity of an aptamer over a free peptide is dependent on the increase in the favorable enthalpy of binding, which is ideally caused by stapling of the peptide or by additional interactions between the aptamer protein and its target. These need to be sufficient to compensate for the destabilization of the scaffold by peptide insertion. These observations will be useful in future aptamer designs. 相似文献
9.
Poudyal H Panchal SK Waanders J Ward L Brown L 《The Journal of nutritional biochemistry》2012,23(2):153-162
Chia seeds contain the essential fatty acid, α-linolenic acid (ALA). This study has assessed whether chia seeds attenuated the metabolic, cardiovascular and hepatic signs of a high-carbohydrate, high-fat (H) diet [carbohydrates, 52% (wt/wt); fat, 24% (wt/wt) with 25% (wt/vol) fructose in drinking water] in rats. Diets of the treatment groups were supplemented with 5% chia seeds after 8 weeks on H diet for a further 8 weeks. Compared with the H rats, chia seed-supplemented rats had improved insulin sensitivity and glucose tolerance, reduced visceral adiposity, decreased hepatic steatosis and reduced cardiac and hepatic inflammation and fibrosis without changes in plasma lipids or blood pressure. Chia seeds induced lipid redistribution with lipid trafficking away from the visceral fat and liver with an increased accumulation in the heart. The stearoyl-CoA desaturase-1 products were depleted in the heart, liver and the adipose tissue of chia seed-supplemented rats together with an increase in the substrate concentrations. The C18:1trans-7 was preferentially stored in the adipose tissue; the relatively inert C18:1n-9 was stored in sensitive organs such as liver and heart and C18:2n-6, the parent fatty acid of the n-6 pathway, was preferentially metabolized. Thus, chia seeds as a source of ALA induce lipid redistribution associated with cardioprotection and hepatoprotection. 相似文献
10.
Gupta L Srivastava K Singh S Puri SK Chauhan PM 《Bioorganic & medicinal chemistry letters》2008,18(11):3306-3309
A series of hybrid molecules 2-[3-(7-Chloro-quinolin-4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-beta-carbolines have been synthesized and screened for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum. Compounds 26, 32, and 34 have shown MIC in the range of 0.05-0.11 microM and are in vitro several folds more active than chloroquine. 相似文献