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排序方式: 共有173条查询结果,搜索用时 140 毫秒
51.
Transdermal drug delivery has made a notable contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. While transdermal delivery systems would appear to provide an attractive solution for local and systemic drug delivery, only a limited number of drugs can be delivered through the outer layer of the skin. The most difficult to deliver in this way are hydrophilic drugs. The aquatic phylum Cnidaria, which includes sea anemones, corals, jellyfish and hydra, is one of the most ancient multicellular phyla that possess stinging cells containing organelles (cnidocysts), comprising a sophisticated injection system. The apparatus is folded within collagenous microcapsules and upon activation injects a thin tubule that immediately penetrates the prey and delivers its contents. Here we show that this natural microscopic injection system can be adapted for systemic transdermal drug delivery once it is isolated from the cells and uploaded with the drug. Using a topically applied gel containing isolated natural sea anemone injectors and the muscarinic receptor antagonist scopolamine, we found that the formulated injectors could penetrate porcine skin and immediately deliver this hydrophilic drug. An in-vivo study in pigs demonstrated, for the first time, rapid systemic delivery of scopolamine, with T(max) of 30 minutes and C(max) 5 times higher than in controls treated topically with a scopolamine-containing gel without cnidocysts. The ability of the formulated natural injection system to penetrate a barrier as thick as the skin and systemically deliver an exogenous compound presents an intriguing and attractive alternative for hydrophilic transdermal drug delivery. 相似文献
52.
The PI3K-AKT, mTOR-p70S6 kinase and AMPK pathways play distinct and critical roles in metabolic regulation. Each pathway is necessary for leptin's anorexigenic effects in the hypothalamus. Here we show that these pathways converge in an integrated phosphorylation cascade to mediate leptin action in the hypothalamus. We identify serine(491) on α2AMPK as the site of convergence and show that p70S6 kinase forms a complex with α2AMPK, resulting in phosphorylation on serine(491). Blocking α2AMPK-serine(491) phosphorylation increases hypothalamic AMPK activity, food intake, and body weight. Serine(491) phosphorylation is necessary for leptin's effects on hypothalamic α2AMPK activity, neuropeptide expression, food intake, and body weight. These results identify an inhibitory AMPK kinase, p70S6 kinase, and demonstrate that AMPK is a substrate for mTOR-p70S6 kinase. This discovery has broad biologic implications since mTOR-p70S6 kinase and AMPK have multiple, fundamental and generally opposing cellular effects that regulate metabolism, cell growth, and development. 相似文献
53.
Shemesh R Toporik A Levine Z Hecht I Rotman G Wool A Dahary D Gofer E Kliger Y Soffer MA Rosenberg A Eshel D Cohen Y 《The Journal of biological chemistry》2008,283(50):34643-34649
G-protein-coupled receptors (GPCRs) represent an important group of targets for pharmaceutical therapeutics. The completion of the human genome revealed a large number of putative GPCRs. However, the identification of their natural ligands, and especially peptides, suffers from low discovery rates, thus impeding development of therapeutics based on these potential drug targets. We describe the discovery of novel GPCR ligands encrypted in the human proteome. Hundreds of potential peptide ligands were predicted by machine learning algorithms. In vitro screening of selected 33 peptides on a set of 152 GPCRs, including a group of designated orphan receptors, was conducted by intracellular calcium measurements and cAMP assays. The screening revealed eight novel peptides as potential agonists that specifically activated six different receptors in a dose-dependent manner. Most of the peptides showed distinct stimulatory patterns targeted at designated and orphan GPCRs. Further analysis demonstrated a significant in vivo effect for one of the peptides in a mouse inflammation model. 相似文献
54.
Georgia Tsagkogeorga Xavier Turon Russell R Hopcroft Marie-Ka Tilak Tamar Feldstein Noa Shenkar Yossi Loya Dorothée Huchon Emmanuel JP Douzery Frédéric Delsuc 《BMC evolutionary biology》2009,9(1):187-16
Background
Tunicates have been recently revealed to be the closest living relatives of vertebrates. Yet, with more than 2500 described species, details of their evolutionary history are still obscure. From a molecular point of view, tunicate phylogenetic relationships have been mostly studied based on analyses of 18S rRNA sequences, which indicate several major clades at odds with the traditional class-level arrangements. Nonetheless, substantial uncertainty remains about the phylogenetic relationships and taxonomic status of key groups such as the Aplousobranchia, Appendicularia, and Thaliacea. 相似文献55.
Although ascidians are conspicuous members of the fouling community not much is known regarding their recruitment patterns in coral reefs. A 1-year study was carried out along the Red Sea coast of Israel to examine the effects of season and spatial distribution on ascidian recruitment to artificial marine structures. In general, autumn and spring were characterized by higher coverage with a significantly higher percentage of cover of Didemnum granulatum in autumn and higher numbers of Herdmania momus in spring. These species contributed the most to similarity between treatments consequently setting the pattern for each group (colonial and solitary). Halocynthia spinosa had significantly higher numbers during winter and Phallusia nigra was absent in spring and winter. H. momus showed a preference for horizontal surfaces. P. nigra and Ascidia cannelata showed a preference for floating units. It is concluded that the ascidian recruitment patterns are species-specific and vary between seasons, orientation and position on the substrata and in the water column. 相似文献
56.
As a result of predicted regional climatic changes the need to select for the more drought-tolerant genotypes (ecotypes) among Mediterranean conifers has become clear. Aleppo pine (Pinus halepensisMill.) seems to be one of the most drought-tolerant pine species. Nevertheless, the existence of geographical trends in their genetic differentiation indicates potentially large differences in drought-tolerance among provenances. This assumption was verified by the finding of large variation among provenances in their internal water relations. Hence, the aim of this study was to compare the ecophysiological behaviour of several Aleppo pine provenances under contrasting climatic conditions. Growth parameters (height and diameter) and survival rate were measured in two provenance trials, one planted under sub-desertic conditions at the northern edge of the Negev desert, and the second under thermo-Mediterranean climatic conditions in the central coastal plains, Israel. Ecophysiological parameters such as: predawn needle water potential, sap flow in the xylem (i.e. transpiration), photosynthesis and water-use efficiency were measured in trees of selected provenances. The results suggest that it is not possible to predict provenance performance under harsh conditions from their performance under more favourable ones. Therefore, selection must be carried out under the exact conditions in which the trees from the resultant selection will be planted. The present study clearly emphasises the need for broad selection programs of P. halepensis. 相似文献
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59.
The use of thermals during the spring and autumn migration across Israel by four species of soaring birds (White Pelican Pelecanus onocrotalus, White Stork Ciconia ciconia, Lesser Spotted Eagle Aquila pomarina and Honey Buzzard Pernis apivorus) was studied by monitoring them with a motorized glider, light aircraft and radar. This is the first study in which soaring migrants have been followed in flight for any length of time and their flight performance has been recorded directly. The birds flew in an average height band between 344 and 1123 m above ground level. Altitude increased from the morning towards noon and decreased again in the afternoon. Average velocities were 29.2 km/h, 38.7 km/h, 50.9 km/h and 45.2 km/h for White Pelicans, White Storks, Lesser Spotted Eagles and Honey Buzzards, respectively. Atmospheric conditions had a major effect on flight velocity. White Storks showed a positive correlation between the flight velocity and the height between the base and top of the thermals. In White Pelicans, there was a correlation between velocity and mean height. Wing load (body mass/wing area) was positively related to the climbing time in thermals and negatively related to the mean height used by a species. There was also a positive, but not significant, relationship between wing load and velocity. Soaring birds appreciably extend the distance covered in migration in relation to the straight line from their breeding to wintering grounds (by 48–91%). The increased distance, caused through circumventing sea areas, ranged between 22–34%, while the increase resulting from soaring accounted for an additional 22–57% of the route. 相似文献
60.
Offen D Gilgun-Sherki Y Barhum Y Benhar M Grinberg L Reich R Melamed E Atlas D 《Journal of neurochemistry》2004,89(5):1241-1251
Increasing evidence suggests that enhanced production of reactive oxygen species (ROS) activates the MAP kinases, c-Jun N-terminal protein kinase (JNK) and mitogen-activated protein kinase MAPK (p38). These phosphorylated intermediates at the stress-activated pathway induce expression of matrix metalloproteinases (MMPs), leading to inflammatory responses and pathological damages involved in the etiology of multiple sclerosis (MS). Here we report that N-acetylcysteine amide (AD4) crosses the blood-brain barrier (BBB), chelates Cu(2+), which catalyzes free radical formation, and prevents ROS-induced activation of JNK, p38 and MMP-9. In the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, oral administration of AD4 drastically reduced the clinical signs, inflammation, MMP-9 activity, and protected axons from demylination damages. In agreement with the in vitro studies, we propose that ROS scavenging by AD4 in MOG-treated animals prevented MMP's induction and subsequent damages through inhibition of MAPK pathway. The low toxicity of AD4 coupled with BBB penetration makes this compound an excellent potential candidate for the therapy of MS and other neurodegenerative disorders. 相似文献