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81.
Ayumu Niida Yoko Kanematsu-Yamaki Tomoko Asakawa Yoshimasa Ishimura Hisashi Fujita Kouta Matsumiya Naoki Nishizawa Yusuke Adachi Taisuke Mochida Kazue Tsuchimori Mariko Yoneyama-Hirozane Junichi Sakamoto Hideki Hirabayashi Hideo Fukui Shiro Takekawa Taiji Asami 《Bioorganic & medicinal chemistry》2018,26(3):566-572
Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23–36), 1) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet-induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (Cmax) and longer time at maximum concentration (Tmax). Compounds 5 and 10, modified with 20?kDa PEG at the N-terminus and eicosanedioic acid at the Lys30 side chain of 1, respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10, with their relatively low Cmax and long Tmax, partially attenuated emesis in dogs compared with 1. These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism. 相似文献
82.
H. Kano N. Yamada C. Saito Y. Murayama-Chiba Y. Asami H. Ito 《Nucleosides, nucleotides & nucleic acids》2018,37(6):353-360
Lactobacillus gasseri PA-3 (PA-3) is a bacterial strain with a strong ability to degrade purine nucleosides. We previously showed that PA-3 incorporates purines in vitro and that oral administration of PA-3 and purines to rats attenuated their absorption of purines. It remains unclear whether these effects of PA-3 depend on bacterial strains. This study therefore compared the abilities of PA-3 and another bacterial strain of L. gasseri, OLL2996, which has shown decreased ability to degrade purine nucleosides in vitro, to incorporate purine nucleosides and to inhibit the absorption of purines fed to rats. Each bacterial strain was incubated in the presence of 14C-adenosine or 14C-inosine and the incorporation of each purine was evaluated by measuring their radioactivity. In vivo, rats were fed 14C-labeled purines along with PA-3 or OLL2996 and the absorption of these 14C-labeled purines was evaluated by analyzing radioactivity of blood samples. PA-3 incorporated about twice as much 14C-adenosine and 14C-inosine as OLL2996. The elevation of radioactivity levels in blood was 10–20% lower in rats treated with PA-3 than in control rats, after feeding with both 14C-adenosine and 14C-inosine as purines. In contrast, treatment with OLL2996 did not have statistically significant effects on radioactivity compared with the control group. These results indicate that the magnitude of bacterial inhibition of purine absorption is dependent on bacterial strain, correlating at least partly with the ability to incorporate and degrade purines. 相似文献
83.
Takahiro Asami Makoto Ishii Ho Namkoong Kazuma Yagi Sadatomo Tasaka Takanori Asakura Shoji Suzuki Tetsuro Kamo Satoshi Okamori Hirofumi Kamata Haiyue Zhang Ahmed E. Hegab Naoki Hasegawa Tomoko Betsuyaku 《Cytotherapy》2018,20(3):302-313
Background
Pneumonia is the fourth leading cause of death worldwide, and Streptococcus pneumoniae is the most commonly associated pathogen. Increasing evidence suggests that mesenchymal stromal cells (MSCs) have anti-inflammatory roles during innate immune responses such as sepsis. However, little is known about the effect of MSCs on pneumococcal pneumonia.Methods
Bone marrow–derived macrophages (BMDMs) were stimulated with various ligands in the presence or absence of MSC-conditioned medium. For in vivo studies, mice intranasally-inoculated with S. pneumoniae were intravenously treated with MSCs or vehicle, and various parameters were assessed.Results
After stimulation with toll-like receptor (TLR) 2, TLR9 or TLR4 ligands, or live S. pneumoniae, TNF-α and interleukin (IL)–6 levels were significantly decreased, whereas IL-10 was significantly increased in BMDMs cultured in MSC-conditioned medium. In mice, MSC treatment decreased the number of neutrophils in bronchoalveolar lavage fluid (BALF) after pneumococcal infection, and this was associated with a decrease in myeloperoxidase activity in the lungs. Levels of proinflammatory cytokines, including TNF-α, IL-6, GM-CSF and IFN-γ, were significantly lower in MSC-treated mice, and the bacterial load in the lung after pneumococcal infection was significantly reduced. In addition, histopathologic analysis confirmed a decrease in the number of cells recruited to the lungs; however, lung edema, protein leakage into the BALF and levels of the antibacterial protein lipocalin 2 in the BALF were comparable between the groups.Conclusions
These results indicate that MSCs could represent a potential therapeutic application for the treatment of pneumonia caused by S. pneumoniae. 相似文献84.
Yoshiko Iida Keiko Sawabe Masayo Kojima Kazuya Oguro Nobuo Nakanishi Hiroyuki Hasegawa 《European journal of biochemistry》2002,269(19):4780-4788
We previously demonstrated in mast cell lines RBL2H3 and FMA3 that tryptophan hydroxylase (TPH) undergoes very fast turnover driven by 26S-proteasomes [Kojima, M., Oguro, K., Sawabe, K., Iida, Y., Ikeda, R., Yamashita, A., Nakanishi, N. & Hasegawa, H. (2000) J. Biochem (Tokyo) 2000, 127, 121-127]. In the present study, we have examined an involvement of TPH phosphorylation in the rapid turnover, using non-neural TPH. The proteasome-driven degradation of TPH in living cells was accelerated by okadaic acid, a protein phosphatase inhibitor. Incorporation of 32P into a 53-kDa protein, which was judged to be TPH based on autoradiography and Western blot analysis using anti-TPH serum and purified TPH as the size marker, was observed in FMA3 cells only in the presence of both okadaic acid and MG132, inhibitors of protein phosphatase and proteasome, respectively. In a cell-free proteasome system constituted mainly of RBL2H3 cell extracts, degradation of exogenous TPH isolated from mastocytoma P-815 cells was inhibited by protein kinase inhibitors KN-62 and K252a but not by H89. Consistent with the inhibitor specificity, the same TPH was phosphorylated by exogenous Ca2+/calmodulin-dependent protein kinase II in the presence of Ca2+ and calmodulin but not by protein kinase A (catalytic subunit). TPH protein thus phosphorylated by Ca2+/calmodulin-dependent protein kinase II was digested more rapidly in the cell-free proteasome system than was the nonphosphorylated enzyme. These results indicated that the phosphorylation of TPH was a prerequisite for proteasome-driven TPH degradation. 相似文献
85.
The amounts of glycolytic intermediates and adenine nucleotides in unfertilized Anthocidaris crassispina eggs and in fertilized eggs or embryos were measured. The determinations on unfertilized and fertilized (30 min) eggs of Pseudocentrotus depressus showed the same results. Calculation of both mass action ratios and free energy changes for each enzymatic step of glycolysis showed that reactions catalysed by α-glucan phosphorylase (EC 2.4.1.1), phosphofructokinase (EC 2.7.1.11) and pyruvate kinase (EC 2.7.1.40) were rate-limiting steps of glycolysis in both unfertilized and fertilized eggs. It also suggested that these three key or rate-limiting enzymes were activated by fertilization. Phosphorylase is activated at fertilization as is also pyruvate kinase. Activation of phosphorylase is also shown by the measurement of the activity in homogenate. Phosphofructokinase showed no increase in activity until 20 min after fertilization, the increase then being closely correlated with a decline in phosphate potential. On the basis of their mass action ratios, none of these rate-limiting enzymes appears to have reached a state of equilibrium by hatching (20 h). The temporal discontinuities in the activation pattern of these three enzymes suggests that no single control mechanism can be operative during the first hour following fertilization. 相似文献
86.
Megumi Narukawa‐Nara Ayako Nakamura Ko Kikuzato Yusuke Kakei Akiko Sato Yuka Mitani Yumiko Yamasaki‐Kokudo Takahiro Ishii Ken‐ichiro Hayashi Tadao Asami Takehiko Ogura Shigeo Yoshida Shozo Fujioka Takashi Kamakura Tsutomu Kawatsu Masanori Tachikawa Kazuo Soeno Yukihisa Shimada 《The Plant journal : for cell and molecular biology》2016,87(3):245-257
We previously reported l ‐α‐aminooxy‐phenylpropionic acid (AOPP) to be an inhibitor of auxin biosynthesis, but its precise molecular target was not identified. In this study we found that AOPP targets TRYPTOPHAN AMINOTRANSFERASE of ARABIDOPSIS 1 (TAA1). We then synthesized 14 novel compounds derived from AOPP to study the structure–activity relationships of TAA1 inhibitors in vitro. The aminooxy and carboxy groups of the compounds were essential for inhibition of TAA1 in vitro. Docking simulation analysis revealed that the inhibitory activity of the compounds was correlated with their binding energy with TAA1. These active compounds reduced the endogenous indole‐3‐acetic acid (IAA) content upon application to Arabidopsis seedlings. Among the compounds, we selected 2‐(aminooxy)‐3‐(naphthalen‐2‐yl)propanoic acid (KOK1169/AONP) and analyzed its activities in vitro and in vivo. Arabidopsis seedlings treated with KOK1169 showed typical auxin‐deficient phenotypes, which were reversed by exogenous IAA. In vitro and in vivo experiments indicated that KOK1169 is more specific for TAA1 than other enzymes, such as phenylalanine ammonia‐lyase. We further tested 41 novel compounds with aminooxy and carboxy groups to which we added protection groups to increase their calculated hydrophobicity. Most of these compounds decreased the endogenous auxin level to a greater degree than the original compounds, and resulted in a maximum reduction of about 90% in the endogenous IAA level in Arabidopsis seedlings. We conclude that the newly developed compounds constitute a class of inhibitors of TAA1. We designated them ‘pyruvamine’. 相似文献
87.
88.
Tryptophan hydroxylase requires Fe2+ for in vitro enzyme activity. In this study, the intracellular activity of tryptophan hydroxylase was assessed by applying 3-hydroxybenzylhydrazine (NSD-1015), an inhibitor of aromatic l-amino acid decarboxylase, to monolayer cultures of RBL2H3 cells, a serotonin producing mast cell line. The effect of manipulating intracellular 'free' iron levels on enzyme activity was analyzed by administration of iron chelators. Desferrioxamine (DFO) suppressed the intracellular enzyme activity. Salicylaldehyde isonicotinoyl hydrazone (SIH) also suppressed enzyme activity, but stimulated it when administered in the Fe-bound form. Hemin also stimulated enzyme activity, which progressively increased over several hours to more than sixfold the initial level. DFO and SIH inhibited the hemin stimulatory effect when administered simultaneously with hemin. Both suppression and stimulation with these chelators took place without a significant decrease or increase in the amount of enzyme. These results indicate that there was an inadequate supply of Fe2+ in the cells to support full activity of tryptophan hydroxylase. 相似文献
89.
Naoki Nishizawa Ayumu Niida Yusuke Adachi Yasushi Masuda Satoshi Kumano Kotaro Yokoyama Tomoko Asakawa Hideki Hirabayashi Nobuyuki Amano Shiro Takekawa Tetsuya Ohtaki Taiji Asami 《Bioorganic & medicinal chemistry letters》2017,27(16):3829-3832
The gastrointestinal peptide, peptide YY3–36 (PYY3–36) and its shorter peptide analogues have been reported to reduce appetite by activating the neuropeptide Y2 receptor (Y2R), which is associated with obesity and other metabolic diseases. A 14-amino acid PYY analogue, Ac-[d-Pro24,Cha27,28,36,Aib31]PYY(23–36) (3), showed high binding affinity and agonist activity for the Y2R, similar to that of PYY3–36, but had weak anorectic activity upon continuous administration in lean mice. Three amino acid substitutions [Pya(4)26, Aib28, Lys30], which contributed to the decreased hydrophobicity of 3, efficiently increased its anorectic activity. The compound containing these three amino acids, Ac-[d-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23–36) (22), exerted more potent and durable food intake suppression than that by PYY3–36 in lean mice, as well as excellent Y2R agonist activity (EC50: 0.20 nM) and good subcutaneous bioavailability (66.6%). The 11-day continuous administration of 22 at 1 mg/kg/day successfully produced antiobese and antidiabetic effects, with more than 20% body weight loss in obese and Type 2 diabetes ob/ob model mice. 相似文献
90.
Naoki Nishizawa Yoko Kanematsu-Yamaki Masaaki Funata Hiroaki Nagai Ayako Shimizu Hisashi Fujita Junichi Sakamoto Shiro Takekawa Taiji Asami 《Bioorganic & medicinal chemistry letters》2017,27(20):4626-4629
Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe19, Nle21, and Arg(Me)24] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of 17 induced anorectic activity in C57BL/6J mice. Owing to its high metabolic stability, 17 would be useful in clarifying the physiological role and therapeutic application of NMU. 相似文献