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61.
Shaoyao-Gancao-Tang (SGT), a traditional Chinese herbal medicine (Kampo formulation) containing Shaoyao (Paeoniae Radix) and Gancao (Glycyrrhizae Radix), is co-administered with laxative sodium picosulfate as a premedication for relieving the pain accompanying colonoscopy. Paeoniflorin (PF), an active glycoside of SGT, is metabolized into the antispasmodic agent paeonimetabolin-I (PM-I) by intestinal bacteria after oral administration. The objective of the present study was to investigate whether the co-administered laxative (sodium picosulfate) influences the metabolism of PF to PM-I by intestinal bacteria. We found that the PF-metabolizing activity of intestinal bacteria in rat feces was significantly reduced to approximately 34% of initial levels by a single sodium picosulfate pretreatment and took approximately 6 days to recover. Repeated administration of SGT after the sodium picosulfate pretreatment significantly shortened the recovery period to around 2 days. Similar results were also observed for plasma PM-I concentration. Since PM-I has muscle relaxant activity, the present results suggest that repetitive administration of SGT after sodium picosulfate pretreatment might be useful to relieve the pain associated with colonoscopy. 相似文献
62.
Hyojin Park Sungwoon Lee Pravesh Shrestha Jihye Kim Jeong Ae Park Yeongrim Ko Young Ho Ban Dae-Young Park Sang-Jun Ha Gou Young Koh Victor Sukbong Hong Naoki Mochizuki Young-Myeong Kim Weontae Lee Young-Guen Kwon 《The Journal of cell biology》2015,211(3):619-637
The phosphoinositide 3-kinase–Akt signaling pathway is essential to many biological processes, including cell proliferation, survival, metabolism, and angiogenesis, under pathophysiological conditions. Although 3-phosphoinositide–dependent kinase 1 (PDK1) is a primary activator of Akt at the plasma membrane, the optimal activation mechanism remains unclear. We report that adhesion molecule with IgG-like domain 2 (AMIGO2) is a novel scaffold protein that regulates PDK1 membrane localization and Akt activation. Loss of AMIGO2 in endothelial cells (ECs) led to apoptosis and inhibition of angiogenesis with Akt inactivation. Amino acid residues 465–474 in AMIGO2 directly bind to the PDK1 pleckstrin homology domain. A synthetic peptide containing the AMIGO2 465–474 residues abrogated the AMIGO2–PDK1 interaction and Akt activation. Moreover, it effectively suppressed pathological angiogenesis in murine tumor and oxygen-induced retinopathy models. These results demonstrate that AMIGO2 is an important regulator of the PDK1–Akt pathway in ECs and suggest that interference of the PDK1–AMIGO2 interaction might be a novel pharmaceutical target for designing an Akt pathway inhibitor. 相似文献
63.
Yoshida M Mori A Morimoto S Kotani E Oka M Notoya K Makino H Ono M Shirasaki M Tada N Fujita H Ban J Ikeda Y Kawamoto T Goto M Kimura H Baba A Yasuma T 《Bioorganic & medicinal chemistry》2011,19(6):1881-1894
The calcium-sensing receptor antagonist (CaSR) has been recognized as a promising target of anabolic agents for treating osteoporosis. In the course of developing a new drug candidate for osteoporosis, we found tetrahydropyrazolopyrimidine derivative 1 to be an orally active CaSR antagonist that stimulated transient PTH secretion in rats. However, compound 1 showed poor physical and chemical stability. In order to work out this compound's chemical stability and further understand its in vivo efficacy, we focused on modifying the 2-position of the tetrahydropyrazolopyrimidine. As a result of chemical modification, we discovered (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate 10m (TAK-075), which showed improved solubility, chemical stability, and in vivo efficacy. Furthermore, we describe that evaluating the active metabolite is important during repeated treatment with short-acting CaSR antagonists. 相似文献
64.
Lapatinib is the only clinically available agent for the treatment of patients with human epidermal growth factor receptor-2 (HER-2) positive tumors that have progressed on treatment with trastuzumab, taxanes and anthracyclines. Moreover, when given with letrozole in postmenopausal patients with estrogen receptor (ER) and HER-2 positive disease it induces clinically meaningful benefit. Recently presented neoadjuvant data suggests an important place for the combination of trastuzumab and lapatinib in the therapy of early HER-2 positive breast cancer. This article reviews the current status and future perspectives of lapatinib. 相似文献
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66.
Raman B Chatani E Kihara M Ban T Sakai M Hasegawa K Naiki H Rao ChM Goto Y 《Biochemistry》2005,44(4):1288-1299
Investigation of factors that modulate amyloid formation of proteins is important to understand and mitigate amyloid-related diseases. To understand the role of electrostatic interactions and the effect of ionic cosolutes, especially anions, on amyloid formation, we have investigated the effect of salts such as NaCl, NaI, NaClO(4), and Na(2)SO(4) on the amyloid fibril growth of beta(2)-microglobulin, the protein involved in dialysis-related amyloidosis. Under acidic conditions, these salts exhibit characteristic optimal concentrations where the fibril growth is favored. The presence of salts leads to an increase in hydrophobicity of the protein as reported by 8-anilinonaphthalene-1-sulfonic acid, indicating that the anion interaction leads to the necessary electrostatic and hydrophobic balance critical for amyloid formation. However, high concentrations of salts tilt the balance to high hydrophobicity, leading to partitioning of the protein to amorphous aggregates. Such amorphous aggregates are not competent for fibril growth. The order of anions based on the lowest concentration at which fibril formation is favored is SO(4)(2)(-) > ClO(4)(-) > I(-) > Cl(-), consistent with the order of their electroselectivity series, suggesting that preferential anion binding, rather than general ionic strength effect, plays an important role in the amyloid fibril growth. Anion binding is also found to stabilize the amyloid fibrils under acidic condition. Interestingly, sulfate promotes amyloid growth of beta(2)-microglobulin at pH between 5 and 6, closer to its isoelectric point. Considering the earlier studies on the role of glycosaminoglycans and proteoglycans (i.e., sulfated polyanions) on amyloid formation, our study suggests that preferential interaction of sulfate ions with amyloidogenic proteins may have biological significance. 相似文献
67.
Sawcer S Ban M Maranian M Yeo TW Compston A Kirby A Daly MJ De Jager PL Walsh E Lander ES Rioux JD Hafler DA Ivinson A Rimmler J Gregory SG Schmidt S Pericak-Vance MA Akesson E Hillert J Datta P Oturai A Ryder LP Harbo HF Spurkland A Myhr KM Laaksonen M Booth D Heard R Stewart G Lincoln R Barcellos LF Hauser SL Oksenberg JR Kenealy SJ Haines JL;International Multiple Sclerosis Genetics Consortium 《American journal of human genetics》2005,77(3):454-467
To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis–associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology. 相似文献
68.
69.
ACE1 polymorphism and progression of SARS 总被引:2,自引:0,他引:2
Itoyama S Keicho N Quy T Phi NC Long HT Ha LD Ban VV Ohashi J Hijikata M Matsushita I Kawana A Yanai H Kirikae T Kuratsuji T Sasazuki T 《Biochemical and biophysical research communications》2004,323(3):1124-1129
We have hypothesized that genetic predisposition influences the progression of SARS. Angiotensin converting enzyme (ACE1) insertion/deletion (I/D) polymorphism was previously reported to show association with the adult respiratory distress syndrome, which is also thought to play a key role in damaging the lung tissues in SARS cases. This time, the polymorphism was genotyped in 44 Vietnamese SARS cases, with 103 healthy controls who had had a contact with the SARS patients and 50 controls without any contact history. SARS cases were divided into either non-hypoxemic or hypoxemic groups. Despite the small sample size, the frequency of the D allele was significantly higher in the hypoxemic group than in the non-hypoxemic group (p=0.013), whereas there was no significant difference between the SARS cases and controls, irrespective of a contact history. ACE1 might be one of the candidate genes that influence the progression of pneumonia in SARS. 相似文献
70.
The effects of bait applications on the overall activity of the Formosan subterranean termite, Coptotermes formosanus Shiraki, in a town of 1.2 km2 were assessed between 2001 and 2003 by using a bait impact index. The index incorporated the amount of baits applied and the distance between bait application loci and the monitoring stations from which termite activity was measured. Even with the collaboration of only 35% of the residents and incomplete treatment records, the bait impact index demonstrated that more baits applied in proximity to monitoring loci significantly caused the decline of C. formosanus activity. 相似文献