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Pharmaceuticals, Volume 6, Issue 9 (September 2013) – 4 articles , Pages 1082-1169

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690 KiB  
Review
Dynamic Cross Talk between S1P and CXCL12 Regulates Hematopoietic Stem Cells Migration, Development and Bone Remodeling
by Karin Golan, Orit Kollet and Tsvee Lapidot
Pharmaceuticals 2013, 6(9), 1145-1169; https://doi.org/10.3390/ph6091145 - 23 Sep 2013
Cited by 32 | Viewed by 8849
Abstract
Hematopoietic stem cells (HSCs) are mostly retained in a quiescent non-motile mode in their bone marrow (BM) niches, shifting to a migratory cycling and differentiating state to replenish the blood with mature leukocytes on demand. The balance between the major chemo-attractants CXCL12, predominantly [...] Read more.
Hematopoietic stem cells (HSCs) are mostly retained in a quiescent non-motile mode in their bone marrow (BM) niches, shifting to a migratory cycling and differentiating state to replenish the blood with mature leukocytes on demand. The balance between the major chemo-attractants CXCL12, predominantly in the BM, and S1P, mainly in the blood, dynamically regulates HSC recruitment to the circulation versus their retention in the BM. During alarm situations, stress-signals induce a decrease in CXCL12 levels in the BM, while S1P levels are rapidly and transiently increased in the circulation, thus favoring mobilization of stem cells as part of host defense and repair mechanisms. Myeloid cytokines, including G-CSF, up-regulate S1P signaling in the BM via the PI3K pathway. Induced CXCL12 secretion from stromal cells via reactive oxygen species (ROS) generation and increased S1P1 expression and ROS signaling in HSCs, all facilitate mobilization. Bone turnover is also modulated by both CXCL12 and S1P, regulating the dynamic BM stromal microenvironment, osteoclasts and stem cell niches which all functionally express CXCL12 and S1P receptors. Overall, CXCL12 and S1P levels in the BM and circulation are synchronized to mutually control HSC motility, leukocyte production and osteoclast/osteoblast bone turnover during homeostasis and stress situations. Full article
(This article belongs to the Special Issue Chemokines)
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346 KiB  
Article
What Goes around Comes around-A Comparative Study of the Influence of Chemical Modifications on the Antimicrobial Properties of Small Cyclic Peptides
by Kathi Scheinpflug, Heike Nikolenko, Igor V. Komarov, Marina Rautenbach and Margitta Dathe
Pharmaceuticals 2013, 6(9), 1130-1144; https://doi.org/10.3390/ph6091130 - 06 Sep 2013
Cited by 57 | Viewed by 7005
Abstract
Tryptophan and arginine-rich cyclic hexapeptides of the type cyclo-RRRWFW combine high antibacterial activity with rapid cell killing kinetics, but show low toxicity in human cell lines. The peptides fulfil the structural requirements for membrane interaction such as high amphipathicity and cationic charge, but [...] Read more.
Tryptophan and arginine-rich cyclic hexapeptides of the type cyclo-RRRWFW combine high antibacterial activity with rapid cell killing kinetics, but show low toxicity in human cell lines. The peptides fulfil the structural requirements for membrane interaction such as high amphipathicity and cationic charge, but membrane permeabilisation, which is the most common mode of action of antimicrobial peptides (AMPs), could not be observed. Our current studies focus on elucidating a putative membrane translocation mechanism whereupon the peptides might interfere with intracellular processes. These investigations require particular analytical tools: fluorescent analogues and peptides bearing appropriate reactive groups were synthesized and characterized in order to be used in confocal laser scanning microscopy and HPLC analysis. We found that minimal changes in both the cationic and hydrophobic domain of the peptides in most cases led to significant reduction of antimicrobial activity and/or changes in the mode of action. However, we were able to identify two modified peptides which exhibited properties similar to those of the cyclic parent hexapeptide and are suitable for subsequent studies on membrane translocation and uptake into bacterial cells. Full article
(This article belongs to the Special Issue Antimicrobial Agents)
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212 KiB  
Review
Clinical Pharmacology of Furosemide in Neonates: A Review
by Gian Maria Pacifici
Pharmaceuticals 2013, 6(9), 1094-1129; https://doi.org/10.3390/ph6091094 - 05 Sep 2013
Cited by 61 | Viewed by 11193
Abstract
Furosemide is the diuretic most used in newborn infants. It blocks the Na+-K+-2Cl symporter in the thick ascending limb of the loop of Henle increasing urinary excretion of Na+ and Cl. This article aimed to [...] Read more.
Furosemide is the diuretic most used in newborn infants. It blocks the Na+-K+-2Cl symporter in the thick ascending limb of the loop of Henle increasing urinary excretion of Na+ and Cl. This article aimed to review the published data on the clinical pharmacology of furosemide in neonates to provide a critical, comprehensive, authoritative and, updated survey on the metabolism, pharmacokinetics, pharmacodynamics and side-effects of furosemide in neonates. The bibliographic search was performed using PubMed and EMBASE databases as search engines; January 2013 was the cutoff point. Furosemide half-life (t1/2) is 6 to 20-fold longer, clearance (Cl) is 1.2 to 14-fold smaller and volume of distribution (Vd) is 1.3 to 6-fold larger than the adult values. t1/2 shortens and Cl increases as the neonatal maturation proceeds. Continuous intravenous infusion of furosemide yields more controlled diuresis than the intermittent intravenous infusion. Furosemide may be administered by inhalation to infants with chronic lung disease to improve pulmonary mechanics. Furosemide stimulates prostaglandin E2 synthesis, a potent dilator of the patent ductus arteriosus, and the administration of furosemide to any preterm infants should be carefully weighed against the risk of precipitation of a symptomatic patent ductus arteriosus. Infants with low birthweight treated with chronic furosemide are at risk for the development of intra-renal calcifications. Full article
(This article belongs to the Special Issue Diuretics)
783 KiB  
Article
Structural and Affinity Analyses of G-Quadruplex DNA Aptamers for Camptothecin Derivatives
by Hiroto Fujita, Yuri Imaizumi, Yuuya Kasahara, Shunsuke Kitadume, Hiroaki Ozaki, Masayasu Kuwahara and Naoki Sugimoto
Pharmaceuticals 2013, 6(9), 1082-1093; https://doi.org/10.3390/ph6091082 - 29 Aug 2013
Cited by 38 | Viewed by 8644
Abstract
We recently selected DNA aptamers that bind to camptothecin (CPT) and CPT derivatives from a 70-mer oligodeoxyribonucleotide (ODN) library using the Systematic Evolution of Ligands by EXponential enrichment (SELEX) method. The target-binding activity of the obtained 70-mer CPT-binding DNA aptamer, termed CA-70, which [...] Read more.
We recently selected DNA aptamers that bind to camptothecin (CPT) and CPT derivatives from a 70-mer oligodeoxyribonucleotide (ODN) library using the Systematic Evolution of Ligands by EXponential enrichment (SELEX) method. The target-binding activity of the obtained 70-mer CPT-binding DNA aptamer, termed CA-70, which contains a 16-mer guanine (G)-core motif (G3TG3TG3T2G3) that forms a three-tiered G-quadruplex, was determined using fluorescence titration. In this study, truncated fragments of CA-70 that all have the G-core motif, CA-40, -20, -19, -18A, -18B, -17, and -16, were carefully analyzed. We found that CA-40 retained the target-binding activity, whereas CA-20, -19, and -18B exhibited little or no binding activities. Further, not only CA-18A but also the shorter length fragments CA-17 and -16 clearly retained the binding activity, indicating that tail strands of the G-quadruplex structure can significantly affect the target binding of G-quadruplex DNA aptamers. Further analyses using circular dichroism (CD) spectroscopy and fluorescence polarization (FP) assay were conducted to investigate the structure and affinity of G-quadruplex DNA aptamers. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
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