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941.
Beneficial effects of l-arginine on reducing obesity: potential mechanisms and important implications for human health 总被引:1,自引:0,他引:1
Jason R. McKnight M. Carey Satterfield Wenjuan S. Jobgen Stephen B. Smith Thomas E. Spencer Cynthia J. Meininger Catherine J. McNeal Guoyao Wu 《Amino acids》2010,39(2):349-357
Over the past 20 years, growing interest in the biochemistry, nutrition, and pharmacology of l-arginine has led to extensive studies to explore its nutritional and therapeutic roles in treating and preventing human metabolic disorders. Emerging evidence shows that dietary l-arginine supplementation reduces adiposity in genetically obese rats, diet-induced obese rats, finishing pigs, and obese human subjects with Type-2 diabetes mellitus. The mechanisms responsible for the beneficial effects of l-arginine are likely complex, but ultimately involve altering the balance of energy intake and expenditure in favor of fat loss or reduced growth of white adipose tissue. Recent studies indicate that l-arginine supplementation stimulates mitochondrial biogenesis and brown adipose tissue development possibly through the enhanced synthesis of cell-signaling molecules (e.g., nitric oxide, carbon monoxide, polyamines, cGMP, and cAMP) as well as the increased expression of genes that promote whole-body oxidation of energy substrates (e.g., glucose and fatty acids) Thus, l-arginine holds great promise as a safe and cost-effective nutrient to reduce adiposity, increase muscle mass, and improve the metabolic profile in animals and humans. 相似文献
942.
Pranali Patel Judy West-Mays Martin Kolb Juan-Carlos Rodrigues Catherine M. Hoff Peter J. Margetts 《Matrix biology》2010,29(2):97-106
Platelet derived growth factor (PDGF) is involved in wound healing in various organ systems. Its potential role in the context of peritoneal injury following long-term peritoneal dialysis is unclear. We used an adenovirus expressing the B chain of PDGF (AdPDGF-B) to assess its effect on pro-fibrotic pathways in the peritoneal membrane. To assess the transforming growth factor (TGF) β independent effects of PDGF, we over-expressed PDGF-B in the peritoneum of either wild-type mice (Smad3+/+) or those with a deletion of the TGFβ signaling protein Smad3 (Smad3?/?). PDGF-B induced sustained angiogenesis in both Smad3+/+ and Smad3?/? mice. Despite increased collagen gene expression, collagen accumulation was transient and fibrogenesis was associated with induction of collagenase activity. We observed epithelial to mesenchymal transition (EMT) involving the peritoneal mesothelial cells, as shown by increased SNAIL and decreased E-Cadherin expression with evidence of mesothelial cells expressing both epithelial and mesenchymal markers. Unlike TGFβ-induced EMT, PDGF-B exposure did not lead to mobilization of the mesothelial cells; they remained as a single monolayer throughout the observation period. This “non-invasive” EMT phenomenon is a novel finding and may have implications concerning the role of EMT in peritoneal fibrosis and injury to other organ systems. The observed effects were similar in Smad3?/? and Smad3+/+ animals, suggesting that the PDGF-B effects were independent of TGFβ or Smad signaling. 相似文献
943.
944.
Molle V Gulten G Vilchèze C Veyron-Churlet R Zanella-Cléon I Sacchettini JC Jacobs WR Kremer L 《Molecular microbiology》2010,78(6):1591-1605
The remarkable survival ability of Mycobacterium tuberculosis in infected hosts is related to the presence of cell wall-associated mycolic acids. Despite their importance, the mechanisms that modulate expression of these lipids in response to environmental changes are unknown. Here we demonstrate that the enoyl-ACP reductase activity of InhA, an essential enzyme of the mycolic acid biosynthetic pathway and the primary target of the anti-tubercular drug isoniazid, is controlled via phosphorylation. Thr-266 is the unique kinase phosphoacceptor, both in vitro and in vivo. The physiological relevance of Thr-266 phosphorylation was demonstrated using inhA phosphoablative (T266A) or phosphomimetic (T266D/E) mutants. Enoyl reductase activity was severely impaired in the mimetic mutants in vitro, as a consequence of a reduced binding affinity to NADH. Importantly, introduction of inhA_T266D/E failed to complement growth and mycolic acid defects of an inhA-thermosensitive Mycobacterium smegmatis strain, in a similar manner to what is observed following isoniazid treatment. This study suggests that phosphorylation of InhA may represent an unusual mechanism that allows M. tuberculosis to regulate its mycolic acid content, thus offering a new approach to future anti-tuberculosis drug development. 相似文献
945.
Tyagarajan S Chakravarty PK Zhou B Taylor B Eid R Fisher MH Parsons WH Wyvratt MJ Lyons KA Klatt T Li X Kumar S Williams B Felix J Priest BT Brochu RM Warren V Smith M Garcia M Kaczorowski GJ Martin WJ Abbadie C McGowan E Jochnowitz N Weber A Duffy JL 《Bioorganic & medicinal chemistry letters》2010,20(24):7479-7482
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain. 相似文献
946.
Robert M. Tynebor Meng-Hsin Chen Swaminathan R. Natarajan Edward A. O’Neill James E. Thompson Catherine E. Fitzgerald Stephen J. O’Keefe James B. Doherty 《Bioorganic & medicinal chemistry letters》2010,20(9):2765-2769
The development and synthesis of potent p38α MAP kinase inhibitors containing a 2H-quinolizin-2-one platform is described. Evolution of the 2H-quinolizin-2-one series from an early lead to solving off target activity and pharmacokinetic issues is also discussed. 相似文献
947.
Liming Dong Joseph Marakovits Xinjun Hou Chuangxing Guo Samantha Greasley Eleanor Dagostino RoseAnn Ferre M. Catherine Johnson Eugenia Kraynov James Thomson Ved Pathak Brion W. Murray 《Bioorganic & medicinal chemistry letters》2010,20(7):2210-2214
Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge–charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand–protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor. 相似文献
948.
Catherine S. Reed Robert W. Huigens Steven A. Rogers Christian Melander 《Bioorganic & medicinal chemistry letters》2010,20(21):6310-6312
The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the best inhibitor inhibiting biofilm development with an IC50 of 13 μM. The most potent promoter of E. coli biofilm formation promoted biofilm development by 321% at 400 μM. 相似文献
949.
Romy F.J. Janser Ranjith K. Meka Zack E. Bryant Enoch A. Adogla Elizabeth K. Vogel Jaimie L. Wharton Cynthia M. Tilley Catherine N. Kaminski Seth L. Ferrey Severine Van slambrouck Wim F.A. Steelant Ingo Janser 《Bioorganic & medicinal chemistry letters》2010,20(6):1848-1850
A series of ethacrynic acid analogues, lacking the α,β-unsaturated carbonyl unit, was synthesized and subsequently evaluated for their ability to inhibit the migration of human breast cancer cells, MCF-7/AZ. Several of the analogues were already active in the low micromolar range, whereas ethacrynic acid itself shows no potential to inhibit the migration of these cancer cells. Preliminary studies show that the presence of one or more methoxy groups at the phenyl ring of ethacrynic acid is important in order for the ethacrynic acid analogues to demonstrate an inhibitory effect on the migration. 相似文献
950.