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991.
Öjemalm K Higuchi T Jiang Y Langel Ü Nilsson I White SH Suga H von Heijne G 《Proceedings of the National Academy of Sciences of the United States of America》2011,108(31):E359-E364
Integral membrane proteins are integrated cotranslationally into the membrane of the endoplasmic reticulum in a process mediated by the Sec61 translocon. Transmembrane α-helices in a translocating polypeptide chain gain access to the surrounding membrane through a lateral gate in the wall of the translocon channel [van den Berg B, et al. (2004) Nature 427:36–44; Zimmer J, et al. (2008) Nature 455:936–943; Egea PF, Stroud RM (2010) Proc Natl Acad Sci USA 107:17182–17187]. To clarify the nature of the membrane-integration process, we have measured the insertion efficiency into the endoplasmic reticulum membrane of model hydrophobic segments containing nonproteinogenic aliphatic and aromatic amino acids. We find that an amino acid’s contribution to the apparent free energy of membrane-insertion is directly proportional to the nonpolar accessible surface area of its side chain, as expected for thermodynamic partitioning between aqueous and nonpolar phases. But unlike bulk-phase partitioning, characterized by a nonpolar solvation parameter of 23 cal/(mol·Å2), the solvation parameter for transfer from translocon to bilayer is 6–10 cal/(mol·Å2), pointing to important differences between translocon-guided partitioning and simple water-to-membrane partitioning. Our results provide compelling evidence for a thermodynamic partitioning model and insights into the physical properties of the translocon. 相似文献
992.
Ehlert FJ Griffin MT Suga H 《The Journal of pharmacology and experimental therapeutics》2011,338(2):658-670
We describe a modification of receptor theory that enables the estimation of relative affinity constants for the inactive state of a G protein-coupled receptor. Our approach includes the traditional parameters of observed affinity (K(obs)) and efficacy (fraction of ligand-receptor complex in the active state, ε) and introduces the concept of the fraction of the ligand-receptor complex in the inactive state (intrinsic inactivity, ε(i)). The relationship between receptor activation and the ligand concentration is known as the stimulus, and the operational model expresses the response as a logistic function of the stimulus. The latter function includes K(obs) and the parameter τ, which is proportional to ε. We introduce the parameter τ(i), which is proportional to ε(i). We have previously shown that the product, K(obs)τ, of one agonist, expressed relative to that of another (intrinsic relative activity, RA(i)), is a relative measure of the affinity constant for the active state of the receptor. In this report, we show that the product, K(obs)τ(i), of one agonist, expressed relative to that of another (intrinsic relative inactivity, RI(i)), is a relative measure of the affinity constant for the inactive state of the receptor. We use computer simulation techniques to verify our analysis and apply our method to the analysis of published data on agonist activity at the M(3) muscarinic receptor. Our method should have widespread application in the analysis of agonist bias in drug discovery programs and in the estimation of a more fundamental relative measure of efficacy (RA(i)/RI(i)). 相似文献
993.
Matsumura Y Mitani A Suga T Kamiya Y Kikuchi T Tanaka S Aino M Noguchi T 《Journal of periodontology》2011,82(11):1623-1631
Background: Recent studies have shown that the 15‐member macrolide antibiotic azithromycin (AZM) not only has antibacterial activity, but also results in the role of immunomodulator. Interleukin (IL)‐8 is an important inflammatory mediator in periodontal disease. However, there have been no reports on the effects of AZM on IL‐8 production from human oral epithelium. Therefore, we investigated the effects of AZM on IL‐8 production in an oral epithelial cell line. Methods: KB cells were stimulated by Escherichia coli or Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) lipopolysaccharide (LPS) with or without AZM. IL‐8 mRNA and protein expression and production in response to LPS were analyzed by quantitative polymerase chain reaction, flow cytometry, and enzyme‐linked immunosorbent assay. The activation of nuclear factor‐kappa B (NF‐κB) and Rac1, which is important for IL‐8 expression, was analyzed by enzyme‐linked immunosorbent assay and Western blotting, respectively. Results: IL‐8 mRNA expression, IL‐8 production, and NF‐κB activation in LPS‐stimulated KB cells were inhibited by the addition of AZM. LPS‐induced Rac1 activation was also suppressed by AZM. Conclusions: This study suggests that AZM inhibits LPS‐induced IL‐8 production in an oral epithelial cell line, in part caused by the suppression of Rac1 and NF‐κB activation. The use of AZM might provide possible benefits in periodontal therapy, with respect to both its antibacterial action and apparent anti‐inflammatory effect. 相似文献
994.
Hazawa M Kudo M Iwata T Saito K Takahashi K Igarashi J Suga H Kashiwakura I 《Investigational new drugs》2012,30(3):862-869
Quorum sensing is defined as the ability of microorganisms to sense their population density via the release of signaling
molecules called autoinducers (AIs). Various types of AI analogs were prepared and their antitumor properties against chronic
myeloid leukemia (CML) K562 cells were investigated. Two AI analogs induced progressive apoptosis with JNK activation and
p21 induction. In addition, this induction of apoptosis is not related to bcr-abl kinase, which sustains CML proliferation.
However, the progression of apoptosis was not inhibited by a caspase family inhibitor. These results suggested that AI analogs
could induce caspase-independent apoptosis in CML K562. 相似文献
995.
S Pérez C Vale E Alonso H Fuwa M Sasaki Y Konno T Goto Y Suga MR Vieytes LM Botana 《Chemical research in toxicology》2012,25(9):1929-1937
The polycyclic ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse biological activities. Gambierol is a marine polycyclic ether toxin, first isolated along with ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound gambierol and the analogues evaluated in this work share the main crucial elements for biological activity, previously described to be the C28═C29 double bond within the H ring and the unsaturated side chain [ Fuwa , H. , Kainuma , N. , Tachibana , K. , Tsukano , C. , Satake , M. , and Sasaki , M. ( 2004 ) Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity . Chem. Eur. J. 10 , 4894 - 4909 ]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of voltage-gated sodium channels (Nav), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a "loss of function" effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of gambierol elicited synchronous calcium oscillations similar to those previously described for gambierol in cultured cerebellar neurons. Neither gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of gambierol exhibited lethality in mice after ip injection of 50 or 80 μg/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for gambierol and its tetracyclic and heptacyclic analogues and indicate a "loss of function" effect on potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of therapies against ciguatera poisoning and potassium channel-related diseases. 相似文献
996.
Shin-ichiro Kojima Minoru Yagi Kimio Asagiri Suguru Fukahori Yoshiaki Tanaka Shinji Ishii Nobuyuki Saikusa Yoshinori Koga Motomu Yoshida Daisuke Masui Naoko Komatsuzaki Shin-ichiro Nakagawa Shuichi Ozono Ken Tanikawa 《Pediatric surgery international》2013,29(7):753-757
Malignant tumors of the urinary bladder in infants are extremely rare. Rhabdomyosarcoma is the most likely tumor in this site, whereas neuroblastoma of the urinary bladder is exceedingly uncommon and is not listed as a differential diagnosis for tumors of this site. We present a case of neuroblastoma arising from the dome of the bladder wall, detected by hematuria. Only six cases of neuroblastoma originating from the bladder, including the present case have been reported. Of the cases, five arose from the dome of the bladder wall. In this report, the differential diagnosis of bladder tumors in children is discussed. A diagnosis of neuroblastoma should be taken into consideration, especially in the case of tumors arising from the dome of the bladder wall despite an uncommon location. 相似文献
997.
998.
Yoshie Kunihiro Munemasa Okada Naofumi Matsunaga Yuichi Sano Shohei Kudomi Kazuyoshi Suga Shoji Kido 《Japanese journal of radiology》2013,31(2):99-104
Purpose
To determine the utility of dual-energy perfusion CT (DEpCT) of non-diseased lung segments, using dual-source CT, in comparison with perfusion single-photon emission computed tomography (SPECT).Materials and methods
28 patients (18 male and 10 female; mean age 63 years; age range 18–86 years) underwent DEpCT and SPECT within a 3-day interval. The presence and location of perfusion defects in each segment of the lungs were evaluated.Results
Perfusion defects were noted in 7 of 361 segments (1.9 %) by DEpCT and in 19 of 361 segments (5.3 %) by perfusion SPECT. DEpCT was in good agreement with perfusion SPECT for 338 of 361 segments (93.6 %). Intraobserver agreement was also good, ranging from 93.4 to 93.6 % (κ = 0.64–0.75, p < 0.01).Conclusion
For non-diseased lung segments, DEpCT correlated well with SPECT. 相似文献999.
Muramatsu S Suga Y Mizuno Y Hasegawa T Tsuchihashi H Matsuba S Kohroh K Yaguchi H Ogawa H 《The British journal of dermatology》2005,152(5):1087-1089
1000.
Inoue T Yoneda K Kakurai M Fujita S Manabe M Demitsu T 《Journal of cutaneous pathology》2002,29(5):305-312
BACKGROUND: Spontaneous regression of solitary mastocytoma is a well-described phenomenon, but its mechanism is unknown. METHODS: Serial-section immunohistochemical analyses were performed on biopsies of a mastocytoma from a Japanese child during the proliferation stage (PS, 7 months of age) and the regression stage (RS, 5 years old). RESULTS: Mast cell (MC) density in RS was markedly decreased (406 cells/mm2) compared to that in PS (3554 cells/mm2). MCs in RS were larger than those in PS. With proliferative cell nuclear antigen (PCNA) staining, 1.7% MCs were positive in PS, whereas no positive MCs were seen in RS. TUNEL-labeling index (LI) in RS (2.8%) increased 1.5-fold in PS (1.9%). With stem cell factor (SCF) staining, 57% of lesional MCs in RS revealed strong cytoplasmic immunoreactivity, whereas only 9% of MCs were positive in PS. Epidermal SCF reactivity was found as intracellular and intercellular patterns in both PS and RS. CONCLUSIONS: Loss of MC proliferating activity, an increase in apoptotic MCs, and increased expression of SCF in remaining MCs in RS may play a role in the involution of mastocytomas. 相似文献