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991.
Shuji Fujii Fuminori Ohsawa Shoya Yamada Ryosuke Shinozaki Ryosuke Fukai Makoto Makishima Shuichi Enomoto Akihiro Tai Hiroki Kakuta 《Bioorganic & medicinal chemistry letters》2010,20(17):5139-5142
Retinoid X receptors (RXRs) function as homo- or heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), which are targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are known as permissive RXR-heterodimers because they are activated by RXR agonists alone. Interestingly, the pattern of RXR-heterodimer activation is different depending on the RXR agonist structure, but the structure–activity relationship has not been reported. Here we show that modification or replacement of the carboxyl group in the acidic domain of RXR agonists has little or no effect on permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and hydroxamic acid (12) analogues were synthesized from the common bromo intermediate 7. Except for 9, these compounds showed RXR full-agonistic activities in the concentration range of 1–10 μM. The order of agonistic activity toward both PPARγ/RXRα and LXRα/RXRα was the same as it was for RXR, that is, 11 > 10 > 12. These results should be useful for the development of RXR agonists with improved bioavailability. 相似文献
992.
Thiolactomycin inhibits d-aspartate oxidase: A novel approach to probing the active site environment
Masumi Katane Yasuaki Saitoh Toshihiko Hanai Masae Sekine Takemitsu Furuchi Nobuhiro Koyama Izumi Nakagome Hiroshi Tomoda Shuichi Hirono Hiroshi Homma 《Biochimie》2010
d-Aspartate oxidase (DDO) and d-amino acid oxidase (DAO) are flavin adenine dinucleotide (FAD)-containing flavoproteins that catalyze the oxidative deamination of d-amino acids. While several functionally and structurally important amino acid residues have been identified in the DAO protein, little is known about the structure–function relationships of DDO. In the search for a potent DDO inhibitor as a novel tool for investigating its structure–function relationships, a large number of biologically active compounds of microbial origin were screened for their ability to inhibit the enzymatic activity of mouse DDO. We discovered several compounds that inhibited the activity of mouse DDO, and one of the compounds identified, thiolactomycin (TLM), was then characterized and evaluated as a novel DDO inhibitor. TLM reversibly inhibited the activity of mouse DDO with a mixed type of inhibition more efficiently than meso-tartrate and malonate, known competitive inhibitors of mammalian DDOs. The selectivity of TLM was investigated using various DDOs and DAOs, and it was found that TLM inhibits not only DDO, but also DAO. Further experiments with apoenzymes of DDO and DAO revealed that TLM is most likely to inhibit the activities of DDO and DAO by competition with both the substrate and the coenzyme, FAD. Structural models of mouse DDO/TLM complexes supported this finding. The binding mode of TLM to DDO was validated further by site-directed mutagenesis of an active site residue, Arg-237. Collectively, our findings show that TLM is a novel, active site-directed DDO inhibitor that will be useful for elucidating the molecular details of the active site environment of DDO. 相似文献
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995.
Masayuki Mori Ken-ichi Yamasaki Satoshi Nakanishi Kazuhiro Kitada Keiichi Higuchi Chiaki Namiki Shuichi Hamada Tadao Serikawa 《Experimental Animals》2003,52(1):31-36
A new beige-like coat color mutant was identified in the ACI/N rat colony. Other features characteristic of beige mutants, such as giant granule cells in various tissues, and prolonged bleeding time were also observed. The genetic complementation test, mating beige-like mutant with the authentic beige mutant rat, DA/Ham-Lystbg, revealed that the mutant gene is allelic to Lystbg. The new beige mutant allele was denoted Lystbg-Kyo. Molecular genetic analysis revealed deletion of exons 28, 29, and 30 of the Lyst gene owing to recombination between L1 elements in the mutant rats. Although the deletion was similar to that identified in DA/Ham-Lystbg rats, the putative deletion break points in L1 elements were different in the two strains. Further characterization of the ACI/N-Lystbg-Kyo rats should make it useful as an animal model for human Chediak-Higashi syndrome. 相似文献
996.
Propionibacterium acnes lipase is an important factor in the pathogenesis of acne, because free fatty acids formed as a result of the effect of P. acnes lipase on sebaceous triglycerides induce severe inflammation. Tetracyclines have been the most common systemic therapy for acne due to their beneficial clinical effects, their inhibition of lipase activity of P. acnes as well as their inhibition of P. acnes chemotaxis. Erythromycin and Jumi-haidoku-to also inhibit the lipase activity of P. acnes. Among P. acnes biotypes and serotypes, stronger P. acnes lipase activities were seen in P. acnes biotype III and serotype II. Conversely, Propionibacterium granulosum is also isolated in acne lesions but has only a faint lipase activity, which might not be of significance. In the future, the degree of P. acnes lipase activity in acne, identified by genetic techniques, needs to be compared to the condition of acne rash. 相似文献
997.
This study examined the persistence rate of resistance training after intervention with progressive resistance training and the long-term changes in self-perceived function as Heath-related quality of life (HRQOL) between a maintaining group (TR) and a detraining group (DT) after the intervention. One hundred sixty-seven persons aged 65 and older participated in this study. We measured SF-36 as indices of HRQOL before intervention (T1), after intervention (T2), and 1 year later (T3).We assessed 135 participants at T3, and, of these, 58 were in TR and 77 were in DT. In TR, T2 scores significantly improved over T1 scores for Physical Functioning, Role Physical, and Mental Health (p<.05-.01). Moreover, in T3 scores, Physical Functioning (p<.01) and Role Physical (p<.05) significantly improved over T1 scores. In DT, T2 scores were significantly higher than T1 scores for Vitality and Mental Health (both p<.01), while T3 scores significantly decreased from T2 scores for Physical Functioning, General Health, Vitality, and Mental Health (p<.05-p<.01). Only Physical Functioning of TR was significantly higher than that of DT in T2. However, Physical Functioning, Role Physical, General Health, Vitality, and Mental Health of TR were significantly higher than that of DT in T3 (p<.05-.01). No subscale scores at T3 were significantly lower than at T1. Our findings suggest that for the elderly, voluntarily continuing training after the structured program has beneficial effects for HRQOL, and the differences in HRQOL with regard to how to spend time after the intervention over the long term. However, it was possible for the HRQOL of the participants to deteriorate, though not significantly, at 1 year after the intervention in comparison to the baseline. This result suggests that the significant HRQOL gains of the DT group for the intervention period are very important. 相似文献
998.
Masayuki Matsui Shuichi Uehara Jingsong Ma 《Flexible Services and Manufacturing Journal》2001,13(4):405-424
This article evaluates the performance of flexible manufacturing systems with finite local buffers and fixed or dynamic routing rules, and addresses the optimal design or system configuration problem of maximizing the system throughput. The costs include machine cost, part (or pallet) cost, and local buffers cost. First, the system throughputs and their behaviors are considered with both queueing network analysis and simulation, and it is shown for a fixed routing model that the system throughput in the case of finite local buffers is greater than in the case of infinite local buffers. For a fixed versus dynamic routing rule, it is also found that the throughput in the former case can be close to the one in the latter case by changing the setting parameters. Next, the design problems of maximizing the system throughput are considered numerically for fixed and dynamic routing cases. Then, it is seen that better combination of design variables is a class of the monotonicity in local buffers, service rates, and routing probabilities. 相似文献
999.
Effect of abscisic acid (ABA) on sugar accumulation in the flesh tissue of peach fruit at the start of the maturation stage 总被引:4,自引:0,他引:4
Kenji Kobashi Sumuko Sugaya Hiroshi Gemma Shuichi Iwahori 《Plant Growth Regulation》2001,35(3):215-223
Experiments were conducted on14C-sorbitol, fructose, and glucose uptakeinto flesh discs, and sorbitol efflux from thediscs, with and without ABA application toexamine the effect of abscisic acid (ABA) onsugar accumulation in peach fruit flesh at thestart of the maturation stage in relation tomembrane transport. Total uptake of14C-sorbitol, fructose, and glucose intoflesh discs was effectively promoted by ABA ata concentration of 10–5
M. PCMBS(p-chloromercuribenzensulfonicacid)-sensitive uptake, which was considered ascarrier-mediated uptake, of sorbitol into thediscs was clearly stimulated by ABA at10–5
M, compared with glucose andfructose uptake. Sorbitol efflux from the discsacross the tonoplast was restricted by ABA at10–5
M. ABA application todeveloping fruit increased sugar accumulationin the fruit. Estimated ABA concentration inthis fruit was approximately 10–5
M. These results indicate that sugar accumulationin peach fruit flesh is stimulated by ABA at aconcentration of 10–5
M both invitro and in vivo. ABA stimulatesuptake of sugars, especially sorbitol, into theflesh by enhancing carrier-mediated transportpossibly across both tonoplast and plasmamembrane. 相似文献
1000.
Loss of mRor1 Enhances the Heart and Skeletal Abnormalities in mRor2-Deficient Mice: Redundant and Pleiotropic Functions of mRor1 and mRor2 Receptor Tyrosine Kinases 下载免费PDF全文
Masashi Nomi Isao Oishi Shuichi Kani Hiroaki Suzuki Takeru Matsuda Akinori Yoda Makiko Kitamura Kyoko Itoh Shigeto Takeuchi Kiyoshi Takeda Shizuo Akira Makoto Ikeya Shinji Takada Yasuhiro Minami 《Molecular and cellular biology》2001,21(24):8329-8335
The mammalian Ror family of receptor tyrosine kinases consists of two structurally related proteins, Ror1 and Ror2. We have shown that mRor2-deficient mice exhibit widespread skeletal abnormalities, ventricular septal defects in the heart, and respiratory dysfunction, leading to neonatal lethality (S. Takeuchi, K. Takeda, I. Oishi, M. Nomi, M. Ikeya, K. Itoh, S. Tamura, T. Ueda, T. Hatta, H. Otani, T. Terashima, S. Takada, H. Yamamura, S. Akira, and Y. Minami, Genes Cells 5:71-78, 2000). Here we show that mRor1-deficient mice have no apparent skeletal or cardiac abnormalities, yet they also die soon after birth due to respiratory dysfunction. Interestingly, mRor1/mRor2 double mutant mice show markedly enhanced skeletal abnormalities compared with mRor2 mutant mice. Furthermore, double mutant mice also exhibit defects not observed in mRor2 mutant mice, including a sternal defect, dysplasia of the symphysis of the pubic bone, and complete transposition of the great arteries. These results indicate that mRor1 and mRor2 interact genetically in skeletal and cardiac development. 相似文献