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191.
192.
Yoshihiro Shiomi Toshimasa Yamauchi Masato Iwabu Miki Okada-Iwabu Ryo Nakayama Yuki Orikawa Yoshichika Yoshioka Koichiro Tanaka Kohjiro Ueki Takashi Kadowaki 《The Journal of biological chemistry》2015,290(23):14567-14581
A novel peroxisome proliferator-activated receptor (PPAR) modulator, Z-551, having both PPARα agonistic and PPARγ antagonistic activities, has been developed for the treatment of obesity and obesity-related metabolic disorders. We examined the effects of Z-551 on obesity and the metabolic disorders in wild-type mice on the high-fat diet (HFD). In mice on the HFD, Z-551 significantly suppressed body weight gain and ameliorated insulin resistance and abnormal glucose and lipid metabolisms. Z-551 inhibited visceral fat mass gain and adipocyte hypertrophy, and reduced molecules involved in fatty acid uptake and synthesis, macrophage infiltration, and inflammation in adipose tissue. Z-551 increased molecules involved in fatty acid combustion, while reduced molecules associated with gluconeogenesis in the liver. Furthermore, Z-551 significantly reduced fasting plasma levels of glucose, triglyceride, free fatty acid, insulin, and leptin. To elucidate the significance of the PPAR combination, we examined the effects of Z-551 in PPARα-deficient mice and those of a synthetic PPARγ antagonist in wild-type mice on the HFD. Both drugs showed similar, but weaker effects on body weight, insulin resistance and specific events provoked in adipose tissue compared with those of Z-551 as described above, except for lack of effects on fasting plasma triglyceride and free fatty acid levels. These findings suggest that Z-551 ameliorates HFD-induced obesity, insulin resistance, and impairment of glucose and lipid metabolisms by PPARα agonistic and PPARγ antagonistic activities, and therefore, might be clinically useful for preventing or treating obesity and obesity-related metabolic disorders such as insulin resistance, type 2 diabetes, and dyslipidemia. 相似文献
193.
Yumi Ueki Michael A Hadders Melanie B Weisser Isha Nasa Paula SoteloParrilla Lauren E Cressey Tanmay Gupta Emil P T Hertz Thomas Kruse Guillermo Montoya A Arockia Jeyaprakash Arminja Kettenbach Susanne M A Lens Jakob Nilsson 《EMBO reports》2021,22(7)
The shugoshin proteins are universal protectors of centromeric cohesin during mitosis and meiosis. The binding of human hSgo1 to the PP2A‐B56 phosphatase through a coiled‐coil (CC) region mediates cohesion protection during mitosis. Here we undertook a structure function analysis of the PP2A‐B56‐hSgo1 complex, revealing unanticipated aspects of complex formation and function. We establish that a highly conserved pocket on the B56 regulatory subunit is required for hSgo1 binding and cohesion protection during mitosis in human somatic cells. Consistent with this, we show that hSgo1 blocks the binding of PP2A‐B56 substrates containing a canonical B56 binding motif. We find that PP2A‐B56 bound to hSgo1 dephosphorylates Cdk1 sites on hSgo1 itself to modulate cohesin interactions. Collectively our work provides important insight into cohesion protection during mitosis. 相似文献
194.
The gastrointestinal tract provides a physical barrier to the diffusion of foreign materials from the lumen into the circulatory system. Impairment of the intercellular tight junction (TJ) shield, which is the major determinant of intestinal barrier function, is associated with various diseases. Dietary flavonoids demonstrate various beneficial effects on our health; however, the information regarding their effects on TJ function is quite limited. To date, four flavonoids — epigallocatechin gallate (EGCG), genistein, myricetin and quercetin — have been reported to exhibit promotive and protective effects on intestinal TJ barrier functions. Genistein, a major soybean isoflavone, protects TJ barrier function against oxidative stress, acetaldehyde, enteric bacteria and inflammatory cytokines. Genistein blocks the tyrosine phosphorylation of the TJ proteins induced by oxidative stress and acetaldehyde, which results in the disassembly of the proteins from the junctional complex. Quercetin, a flavonol, enhances intestinal TJ barrier function through the assembly and expression of TJ proteins. The change in phosphorylation status is responsible for the quercetin-mediated assembly of TJ proteins. TJ protein induction has an additional role in this effect. This review presents the recent advances in our understanding of the flavonoid-mediated promotive and protective effects on intestinal TJ barrier function with a particular focus on intracellular molecular mechanisms. 相似文献
195.
Komatsu K Hashimoto M Maejima K Shiraishi T Neriya Y Miura C Minato N Okano Y Sugawara K Yamaji Y Namba S 《Molecular plant-microbe interactions : MPMI》2011,24(4):408-420
Systemic necrosis is the most destructive symptom induced by plant pathogens. We previously identified amino acid 1154, in the polymerase domain (POL) of RNA-dependent RNA polymerase (RdRp) of Plantago asiatica mosaic virus (PlAMV), which affects PlAMV-induced systemic necrosis in Nicotiana benthamiana. By point-mutation analysis, we show that amino acid 1,154 alone is not sufficient for induction of necrotic symptoms. However, PlAMV replicons that can express only RdRp, derived from a necrosis-inducing PlAMV isolate, retain their ability to induce necrosis, and transient expression of PlAMV-encoded proteins indicated that the necrosis-eliciting activity resides in RdRp. Moreover, inducible-overexpression analysis demonstrated that the necrosis was induced in an RdRp dose-dependent manner. In addition, during PlAMV infection, necrotic symptoms are associated with high levels of RdRp accumulation. Surprisingly, necrosis-eliciting activity resides in the helicase domain (HEL), not in the amino acid 1,154-containing POL, of RdRp, and this activity was observed even in HELs of PlAMV isolates of which infection does not cause necrosis. Moreover, HEL-induced necrosis had characteristics similar to those induced by PlAMV infection. Overall, our data suggest that necrotic symptoms induced by PlAMV infection depend on the accumulation of a non-isolate specific elicitor HEL (even from nonnecrosis isolates), whose expression is indirectly regulated by amino acid 1,154 that controls replication. 相似文献
196.
Wada K Maeda YY Watanabe K Oshio T Ueda T Takahashi G Yokohama M Saito J Seki Y Takahama S Ishii R Shitara H Taya C Yonekawa H Kikkawa Y 《Mammalian genome》2011,22(11-12):693-702
The Rinshoken cataract (rct) mutation, which causes congenital cataracts, is a recessive mutation found in SJL/J mice. All mutants present with opacity in the lens by 2?months of age. The rct locus was mapped to a 1.6-Mb region in Chr 4 that contains the Foxe3 gene. This gene is responsible for cataracts in humans and mice, and it plays a crucial role in the development of the lens. Furthermore, mutation of Foxe3 causes various ocular defects. We sequenced the genomic region of Foxe3, including the coding exons and UTRs; however, no mutations were discovered in these regions. Because there were no differences in Foxe3 sequences between the rct/rct and wild-type mice, we inferred that a mutation was located in the regulatory regions of the Foxe3 gene. To test this possibility, we sequenced a 5' noncoding region that is highly conserved among vertebrates and is predicted to be the major enhancer of Foxe3. This analysis revealed a deletion of 22-bp located approximately 3.2-kb upstream of the start codon of Foxe3 in rct mice. Moreover, we demonstrated by RT-PCR and in situ hybridization that the rct mutant has reduced expression of Foxe3 in the lens during development. We therefore suggest that cataracts in rct mice are caused by reduced Foxe3 expression in the lens and that this decreased expression is a result of a deletion in a cis-acting regulatory element. 相似文献
197.
To H Yoshimatsu H Tomonari M Ida H Tsurumoto T Tsuji Y Sonemoto E Shimasaki N Koyanagi S Sasaki H Ieiri I Higuchi S Kawakami A Ueki Y Eguchi K 《Chronobiology international》2011,28(3):267-274
Methotrexate (MTX) is the most important drug for treating rheumatoid arthritis (RA). It has been stated that cytokines play an important role in the pathogenesis of RA, and that cytokine levels increase and show 24-h rhythms in RA patients. Previously, we found that arthritis was relieved after the administration of MTX at specific times in synchronization with the 24-h rhythm of tumor necrosis factor (TNF)-α in collagen-induced arthritis (CIA) animals. Based on our findings in an earlier study of the dosing time-dependent effects of MTX in MRL/lpr mice, which develop autoimmune disorders that share similarities with human RA, we examined here the utility of MTX chronotherapy in Japanese RA patients. In an initial animal modeling study, we collected blood from MRL/lpr mice at different times (2, 6, 10, 14, 18, or 22 hours after the light was turned on [HALO]), and we measured TNF-α mRNA expression in leukocytes. MTX was administered to the mice at two different dosing times (6 or 18 HALO), and various blood parameters were measured to estimate arthritis activity. TNF-α mRNA levels showed a clear 24-h rhythm with a peak at 22 HALO and a trough at 18 HALO after RA had developed. In these MRL/lpr mice, inflammation and TNF-α were markedly reduced when the MTX dosing time was matched to the time (18 HALO) when the TNF-α level began to increase. We then applied these findings to Japanese RA patients by switching them from the standard MTX three times/wk (day 1: after breakfast and supper; day 2: after breakfast schedule), to chronotherapy, in which the dose and number of doses/wk were not changed but MTX was administered once-a-day at bedtime. Disease Activity Score (DAS)28, modified health assessment questionnaire (MHAQ), and adverse effects were assessed. With MTX chronotherapy, DAS28, which is commonly used to quantitatively assess RA symptoms, was significantly improved at all follow-up clinical visit times compared with the baseline (vs. 1 mo: p?=?.0197, 2 mos: p?=?.0107, 3 mos: p?=?.0087). Significant symptom recovery was observed in 41.2% of patients, and 23.5% of patients achieved clinical remission during the 3 mos of follow-up. Functional capacity of RA patients, as indicated by the MHAQ, was markedly improved by chronotherapy. There were no severe adverse effects. Thus, we demonstrated (i) inflammation and plasma TNF-α concentrations were significantly reduced in MRL/lpr mice treated with MTX at 18 HALO, the time when TNF-α mRNA level began to increase; and (ii) MTX bedtime chronotherapy was safe, markedly reduced disease activity, and improved the functional capacity of RA patients. The findings on RA patients show that bedtime MTX chronotherapy can improve RA symptoms compared to the current standard dosing methods. 相似文献
198.
Teno N Gohda K Wanaka K Sueda T Tsuda Y 《Bioorganic & medicinal chemistry letters》2011,21(21):6305-6309
Lysine-nitrile derivatives having a trisubstituted benzene, which belongs to a new chemical class, were prepared and tested for inhibitory activities against plasmin and the highly homologous plasma kallikrein and urokinase. The use of the novel chemotype in the development of plasmin inhibitors has been demonstrated by derivatives of compound 9. 相似文献
199.
Kurata H Otsuki K Kusumi K Kurono M Terakado M Seko T Mizuno H Ono T Hagiya H Minami M Nakade S Habashita H 《Bioorganic & medicinal chemistry letters》2011,21(5):1390-1393
Structure-activity relationship of sphingosine-1-phosphate receptor agonist was examined. In terms of reducing the flexibility of molecule, hit compound 1 was modified to improve S1P1 agonistic activity as well as selectivity over S1P3 agonistic activity. Novel S1P agonists with cinnamyl scaffold or 1,2,5,6-tetrahydropyridine scaffold were identified. 相似文献
200.
Hirata T Terai T Komatsu T Hanaoka K Nagano T 《Bioorganic & medicinal chemistry letters》2011,21(20):6090-6093
We have developed a red-emitting fluorescent K(+) probe, B3TAC, which also shows a wavelength shift upon binding to K(+). The probe was synthesized by conjugating a cryptand-based chelator, 2-triazacryptand [2,2,3]-1-(2-methoxyethoxy)benzene (TAC), to position 3 of the BODIPY fluorophore through a styryl linker. In water-acetonitrile mixed solvent, it responded to K(+) in the physiological concentration range with high selectivity over Na(+) and other metal ions. B3TAC is potentially useful for measuring cellular K(+) ion concentration, as well as for simple, naked-eye detection of K(+) in solution. 相似文献