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241.
Niisato N Hasegawa I Tokuda S Taruno A Nakajima K Miyazaki H Iwasaki Y Marunaka Y 《Biochemical and biophysical research communications》2007,356(4):1050-1055
Neltenexine has been applied to human lung diseases such as chronic obstructive pulmonary disease (COPD) as a mucolytic agent. However, we have no information on the neltenexine action in bronchial epithelial cells. We studied the neltenexine action on the ion transport in human submucosal serous Calu-3 cells. Under a hyper-secreting condition caused by terbutaline (a beta2-adrenergic agonist), neltenexine diminished anion secretion by inhibiting the Cl- and HCO3- uptake via Na+/K+/2Cl- cotransporter and Na+/HCO3- cotransporter without blockade of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, and also diminished anion secretion via stimulation of Cl-/HCO3- exchanger, which facilitates the extrusion of more CFTR-permeant anion, Cl-, with the uptake of less CFTR-permeant anion, HCO3-. Thus, neltenexine reduced the hyper-secretion to keep an appropriate fluid level in the airway, providing a possibility that neltenexine can be an effective drug in airway obstructive diseases by decreasing the airway resistance under a hyper-secreting condition. 相似文献
242.
243.
Miura K Yoshiura K Miura S Shimada T Yamasaki K Yoshida A Nakayama D Shibata Y Niikawa N Masuzaki H 《Human genetics》2007,121(5):631-633
Here we provided the first genetic evidence for an association between the degree of apocrine colostrum secretion and human
earwax type. Genotyping at the earwax-type locus, rs17822931 within the ABCC11 gene, revealed that 155 of 225 Japanese women were dry-type and 70 wet-type. Frequency of women without colostrum among dry-type
women was significantly higher than that among wet-type women (P < 0.0002), and the measurable colostrum volume in dry-type women was significantly smaller than in wet-type women (P = 0.0341). 相似文献
244.
Kajiya M Hirota M Inai Y Kiyooka T Morimoto T Iwasaki T Endo K Mohri S Shimizu J Yada T Ogasawara Y Naruse K Ohe T Kajiya F 《American journal of physiology. Heart and circulatory physiology》2007,292(6):H2737-H2744
Pulmonary hypertension (PH) causes right ventricular (RV) hypertrophy and, according to the extent of pressure overload, eventual heart failure. We tested the hypothesis that the mechanical stress in PH-RV impairs the vasoreactivity of the RV coronary microvessels of different sizes with increased superoxide levels. Five-week-old male Sprague-Dawley rats were injected with monocrotaline (n=126) to induce PH or with saline as controls (n=114). After 3 wk, coronary arterioles (diameter = 30-100 microm) and small arteries (diameter = 100-200 microm) in the RV were visualized using intravital videomicroscopy. We evaluated ACh-induced vasodilation alone, in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME), in the presence of tetraethylammonium (TEA) or catalase with or without L-NAME, and in the presence of SOD. The degree of suppression in vasodilation by L-NAME and TEA was used as indexes of the contributions of endothelial nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), respectively. In PH rats, ACh-induced vasodilation was significantly attenuated in both arterioles and small arteries, especially in arterioles. This decreased vasodilation was largely attributable to reduced NO-mediated vasoreactivity, whereas the EDHF-mediated vasodilation was relatively robust. The suppressive effect on arteriolar vasodilation by catalase was similar to TEA in both groups. Superoxide, as measured by lucigenin chemiluminescence, was significantly elevated in the RV tissues in PH. SOD significantly ameliorated the impairment of ACh-induced vasodilation in PH. Robust EDHF function will play a protective role in preserving coronary microvascular homeostasis in the event of NO dysfunction with increased superoxide levels. 相似文献
245.
Shi L Bielawski J Mu J Dong H Teng C Zhang J Yang X Tomishige N Hanada K Hannun YA Zuo J 《Cell research》2007,17(12):1030-1040
Sphingolipids have been suggested to act as second messengers for an array of cellular signaling activities in plant cells, including stress responses and programmed cell death (PCD). However, the mechanisms underpinning these processes are not well understood. Here, we report that an Arabidopsis mutant, fumonisin B1 r_esistant11-1 (/br11-1), which fails to generate reactive oxygen intermediates (ROIs), is incapable of initiating PCD when the mutant is challenged by fumonisin B l (FB0, a specific inhibitor of ceramide synthase. Molecular analysis indicated that FBR11 encodes a long-chain base 1 (LCB 1) subunit of serine palmitoyltransferase (SPT), which catalyzes the first rate-limiting step of de novo sphingolipid synthesis. Mass spectrometric analysis of the sphingolipid concentrations revealed that whereas the fbr11-1 mutation did not affect basal levels of sphingoid bases, the mutant showed attenuated formation of sphingoid bases in response to FBl. By a direct feeding experiment, we show that the free sphingoid bases dihydrosphingosine, phytosphingosine and sphingosine efficiently induce ROI generation followed by cell death. Conversely, ROI generation and cell death induced by dihydrosphingosine were specifically blocked by its phosphorylated form dihydrosphingosine- 1-phosphate in a dosedependent manner, suggesting that the maintenance of homeostasis between a free sphingoid base and its phosphorylated derivative is critical to determining the cell fate. Because alterations of the sphingolipid level occur prior to the ROI production, we propose that the free sphingoid bases are involved in the control of PCD in Arabidopsis, presumably through the regulation of the ROI level upon receiving different developmental or environmental cues. 相似文献
246.
Yagi N Yano Y Hatanaka K Yokoyama Y Okuno H 《Bioorganic & medicinal chemistry letters》2007,17(9):2590-2593
A novel lipid analog based on amino acids for liposome modification was developed. It consisted of three different kinds of amino acid derivatives and two fatty acids, and can react directly with the peptide synthesized first on resin by Fmoc solid-phase synthesis. In this study, lipid analog conjugated with HIV-TAT peptide (domain of human immunodeficiency virus TAT protein) was synthesized and successfully incorporated into liposome. The liposome containing the lipopeptide bearing HIV-TAT exhibited efficient cellular uptake. 相似文献
247.
Sodium zinc dihydrolipoylhistidinate (DHLHZn) is a compound of Zn(2+)/dihydrolipoic acid derivate complex, which was developed for cosmetic/medical use. To characterize DHLHZn as a novel skin-lightening agent, inhibitory actions of DHLHZn on tyrosinase (including its reaction pathway) have been elucidated in this study. In a B16 melanoma cell system, DHLHZn was active in suppressing the synthesis of melanins as well as alpha-arbutin, well known as a depigmenting drug. Furthermore, in a tyrosinase assay, DHLHZn showed stronger inhibitory effect on DOPAchrome formation than other tyrosinase inhibitors such as kojic acid. Our previous report demonstrated that the sulfhydryl groups of lipoyl motif react with DOPAquinone to form lipoyl DOPA conjugates. We therefore postulated that conjugated products between DHLHZn and DOPAquinone might be formed. Upon reaction of DHLHZn with L-DOPA following tyrosinase-catalyzed oxidation, the formation of DHLH DOPA conjugated products was confirmed by HPLC-tandem mass spectrometry using reserpine as the internal standard. In addition, the inhibitory kinetics analyzed by a Lineweaver-Burk plot exhibited the reversibility of DHLHZn as a competitive inhibitor with a KI value of 0.35 microM. These results indicate that this covalent reaction might contribute to alternating DOPAquinone, which is a tyrosinase reaction product, and result in the competitive inhibitory effect of DHLHZn on DOPAchrome formation. DHLHZn may thus serve as a potentially effective skin-lightening agent, an effectiveness that is based on the compound's covalent scavenging of DOPAquinone resulting in depigmentation. 相似文献
248.
249.
Design, synthesis, and biological activity of folate receptor-targeted prodrugs of thiolate histone deacetylase inhibitors 总被引:1,自引:0,他引:1
Suzuki T Hisakawa S Itoh Y Suzuki N Takahashi K Kawahata M Yamaguchi K Nakagawa H Miyata N 《Bioorganic & medicinal chemistry letters》2007,17(15):4208-4212
Aiming to develop selective anticancer drugs, we designed and synthesized three disulfides bearing a folic acid moiety as candidate folate receptor (FR)-targeted prodrugs of thiolate histone deacetylase inhibitors. Among them, compound 1 displayed growth-inhibitory activity toward folate receptor-positive MCF-7 breast cancer cells. The activity of 1 was significantly reduced by free folic acid, suggesting that cellular uptake of 1 is mediated by FR. 相似文献
250.
Teno N Miyake T Ehara T Irie O Sakaki J Ohmori O Gunji H Matsuura N Masuya K Hitomi Y Nonomura K Horiuchi M Gohda K Iwasaki A Umemura I Tada S Kometani M Iwasaki G Cowan-Jacob SW Missbach M Lattmann R Betschart C 《Bioorganic & medicinal chemistry letters》2007,17(22):6096-6100
Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20. 相似文献