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121.
Carbenoxolone inhibits TRPV4 channel‐initiated oxidative urothelial injury and ameliorates cyclophosphamide‐induced bladder dysfunction 下载免费PDF全文
Xiling Zhang Shan Gao Masayoshi Tanaka Zhen Zhang Yanru Huang Takahiko Mitsui Manabu Kamiyama Schuichi Koizumi Jianglin Fan Masayuki Takeda Jian Yao 《Journal of cellular and molecular medicine》2017,21(9):1791-1802
Carbenoxolone (CBX) is a clinically prescribed drug for the treatment of digestive ulcer and inflammation. It is also a widely used pharmacological inhibitor of several channels in basic research. Given that the overactivity of several channels, including those inhibitable by CBX, underlies bladder dysfunction, we tested the potential therapeutic application and mechanism of CBX in the treatment of voiding dysfunction. In a mouse model of cystitis induced by cyclophosphamide (CYP), CBX administration prevented the CYP‐elicited increase in bladder weight, oedema, haemorrhage, and urothelial injury. CBX also greatly improved micturition pattern, as manifested by the apparently decreased micturition frequency and increased micturition volume. Western blot results showed that CBX suppressed CYP‐induced increase in protein carbonyls, COX‐2, and iNOS. Further analysis using cultured urothelial cells revealed that acrolein, the major metabolite of CYP, caused protein oxidation, p38 activation, and urothelial injury. These effects of acrolein were reproduced by TRPV4 agonists and significantly prevented by antioxidant NAC, p38 inhibitor SB203580, TRPV4 antagonist RN‐1734, and CBX. Further studies showed that CBX potently suppressed TRPV4 agonist‐initiated calcium influx and subsequent cell injury. CBX attenuated CYP‐induced cystitis in vivo and reduced acrolein‐induced cell injury in vitro, through mechanisms involving inhibition of TRPV4 channels and attenuation of the channel‐mediated oxidative stress. CBX might be a promising agent for the treatment of bladder dysfunction. 相似文献
122.
Takahiko Kojima Hironori Kitaguchi Mikio Yasutake Yoshihisa Matsuda 《Inorganica chimica acta》2005,358(13):3592-3600
Two kinds of Cu(II) complexes having 2,2′-bipyridine derivatives with two 1-naphthoylamide groups or two ethyl dimethylmalonylamide moieties at 6 and 6′ positions as ligands were prepared and characterized by X-ray crystallography and spectroscopic methods. Those ligands bound to the Cu(II) centers in a tetradentate fashion including two amide oxygen atoms in the equatorial planes. Those complexes were found to recognize carboxylic acids as guest molecules by coordination and additional non-covalent interactions, including intramolecular π-π interactions or hydrogen bonding. 相似文献
123.
Moree WJ Kataoka K Ramirez-Weinhouse MM Shiota T Imai M Tsutsumi T Sudo M Endo N Muroga Y Hada T Fanning D Saunders J Kato Y Myers PL Tarby CM 《Bioorganic & medicinal chemistry letters》2008,18(6):1869-1873
SAR studies were conducted around lead compound 1 using high-throughput parallel solution and solid phase synthesis. Our lead optimization efforts led to the identification of several CCR2b antagonists with potent activity in both binding and functional assays [Compound 71 CCR2b Binding IC(50) 3.2 nM; MCP-1-Induced Chemotaxis IC(50) 0.83 nM; Ca(2+) Flux IC(50) 7.5 nM]. 相似文献
124.
Two new species of the genus Corollospora, namely, C. anglusa sp. nov. with its anamorph Varicosporina anglusa sp. nov. and C. portsaidica sp. nov., which were isolated from the coast of the Mediterranean Sea in Egypt, are described in this article based on morphological
and molecular evidence. The two new species have one-septate ascospores. Corollospora anglusa resembles C. gracilis by having narrow one-septate hyaline ascospores; however, they differ in ascomata and ascospore dimensions and in pure culture
characteristics. Single-ascospore culture of C. anglusa produces the conidia of its anamorph, whereas an anamorph has not been reported for C. gracilis. Varicosporina anglusa differs from the other two known Varicosporina species by having conidial branches that are filamentous, rectangularly branched, hypha like, and disarticulated into two-
or one-celled fragments. Corollospora portsaidica is morphologically similar to C. cinnamomea, but the two species differ in the dimensions, shape, and ornamentation of the ascospores. The new Corollospora species were confirmed to be divergent from other similar Corollospora species based on phylogenetic analyses of partial sequences of the LSU rDNA region. 相似文献
125.
Maeda K Das D Ogata-Aoki H Nakata H Miyakawa T Tojo Y Norman R Takaoka Y Ding J Arnold GF Arnold E Mitsuya H 《The Journal of biological chemistry》2006,281(18):12688-12698
We have characterized the structural and molecular interactions of CC-chemokine receptor 5 (CCR5) with three CCR5 inhibitors active against R5 human immunodeficiency virus type 1 (HIV-1) including the potent in vitro and in vivo CCR5 inhibitor aplaviroc (AVC). The data obtained with saturation binding assays and structural analyses delineated the key interactions responsible for the binding of CCR5 inhibitors with CCR5 and illustrated that their binding site is located in a predominantly lipophilic pocket in the interface of extracellular loops and within the upper transmembrane (TM) domain of CCR5. Mutations in the CCR5 binding sites of AVC decreased gp120 binding to CCR5 and the susceptibility to HIV-1 infection, although mutations in TM4 and TM5 that also decreased gp120 binding and HIV-1 infectivity had less effects on the binding of CC-chemokines, suggesting that CCR5 inhibition targeting appropriate regions might render the inhibition highly HIV-1-specific while preserving the CC chemokine-CCR5 interactions. The present data delineating residue by residue interactions of CCR5 with CCR5 inhibitors should not only help design more potent and more HIV-1-specific CCR5 inhibitors, but also give new insights into the dynamics of CC-chemokine-CCR5 interactions and the mechanisms of CCR5 involvement in the process of cellular entry of HIV-1. 相似文献
126.
CuZn-SOD deficiency causes ApoB degradation and induces hepatic lipid accumulation by impaired lipoprotein secretion in mice 总被引:3,自引:0,他引:3
Elevated hepatic reactive oxygen species play an important role in pathogenesis of liver diseases, such as alcohol-induced liver injury, hepatitis C virus infection, and nonalcoholic steatohepatitis. In the present study, we investigated and compared the hepatic lipid metabolisms of liver-specific Sod2 (superoxide dismutase 2) knock-out (Sod2 KO), Sod1 knock-out (Sod1 KO), and Sod1/liver-specific Sod2 double knock-out mice (double KO). We observed significant increases in lipid peroxidation and triglyceride (TG) in the liver of Sod1 KO and double KO mice but not in the liver of Sod2 KO mice. We also found that high fat diet enhanced fatty changes of the liver in Sod1 KO and double KO mice but not in Sod2 KO mice. These data indicated that CuZn-SOD deficiency caused lipid accumulation in the liver. To investigate the molecular mechanism of hepatic lipid accumulation in CuZn-SOD-deficient mice, we measured TG secretion rate from liver using Triton WR1339. We found significant decrease of TG secretion in CuZn-SOD-deficient mice. Furthermore, we observed marked degradation of apolipoprotein B (apoB) in the liver and plasma of CuZn-SOD-deficient mice, indicating that degradation of apoB impairs secretion of lipoprotein from the liver. Our data suggest that oxidative stress enhances hepatic lipid accumulation by impaired lipoprotein secretion due to the degradation of apoB in liver. 相似文献
127.
Murakami K Murata N Noda Y Tahara S Kaneko T Kinoshita N Hatsuta H Murayama S Barnham KJ Irie K Shirasawa T Shimizu T 《The Journal of biological chemistry》2011,286(52):44557-44568
Oxidative stress is closely linked to the pathogenesis of neurodegeneration. Soluble amyloid β (Aβ) oligomers cause cognitive impairment and synaptic dysfunction in Alzheimer disease (AD). However, the relationship between oligomers, oxidative stress, and their localization during disease progression is uncertain. Our previous study demonstrated that mice deficient in cytoplasmic copper/zinc superoxide dismutase (CuZn-SOD, SOD1) have features of drusen formation, a hallmark of age-related macular degeneration (Imamura, Y., Noda, S., Hashizume, K., Shinoda, K., Yamaguchi, M., Uchiyama, S., Shimizu, T., Mizushima, Y., Shirasawa, T., and Tsubota, K. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 11282-11287). Amyloid assembly has been implicated as a common mechanism of plaque and drusen formation. Here, we show that Sod1 deficiency in an amyloid precursor protein-overexpressing mouse model (AD mouse, Tg2576) accelerated Aβ oligomerization and memory impairment as compared with control AD mouse and that these phenomena were basically mediated by oxidative damage. The increased plaque and neuronal inflammation were accompanied by the generation of N(ε)-carboxymethyl lysine in advanced glycation end products, a rapid marker of oxidative damage, induced by Sod1 gene-dependent reduction. The Sod1 deletion also caused Tau phosphorylation and the lower levels of synaptophysin. Furthermore, the levels of SOD1 were significantly decreased in human AD patients rather than non-AD age-matched individuals, but mitochondrial SOD (Mn-SOD, SOD2) and extracellular SOD (CuZn-SOD, SOD3) were not. These findings suggest that cytoplasmic superoxide radical plays a critical role in the pathogenesis of AD. Activation of Sod1 may be a therapeutic strategy for the inhibition of AD progression. 相似文献
128.
The atomic structure of rice dwarf virus reveals the self-assembly mechanism of component proteins 总被引:5,自引:0,他引:5
Nakagawa A Miyazaki N Taka J Naitow H Ogawa A Fujimoto Z Mizuno H Higashi T Watanabe Y Omura T Cheng RH Tsukihara T 《Structure (London, England : 1993)》2003,11(10):1227-1238
Rice dwarf virus (RDV), the causal agent of rice dwarf disease, is a member of the genus Phytoreovirus in the family Reoviridae. RDV is a double-shelled virus with a molecular mass of approximately 70 million Dalton. This virus is widely prevalent and is one of the viruses that cause the most economic damage in many Asian countries. The atomic structure of RDV was determined at 3.5 A resolution by X-ray crystallography. The double-shelled structure consists of two different proteins, the core protein P3 and the outer shell protein P8. The atomic structure shows structural and electrostatic complementarities between both homologous (P3-P3 and P8-P8) and heterologous (P3-P8) interactions, as well as overall conformational changes found in P3-P3 dimer caused by the insertion of amino-terminal loop regions of one of the P3 protein into the other. These interactions suggest how the 900 protein components are built into a higher-ordered virus core structure. 相似文献
129.
130.
Takahiko Matsushita Wataru Takada Kota Igarashi Kentaro Naruchi Risho Miyoshi Fayna Garcia-Martin Maho Amano Hiroshi Hinou Shin-Ichiro Nishimura 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014