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121.
Ilić M Kontogiorgis C Hadjipavlou-Litina D Ilaš J Kikelj D 《Bioorganic & medicinal chemistry letters》2011,21(16):4705-4709
Vascular oxidative stress, endothelial injury, and thrombosis are intertwined processes that display a synergistic pathological effect in many cardiovascular diseases. Antithrombotic therapy with anticoagulant and/or antiplatelet agents, combined with interventions against vascular oxidative stress and/or inflammation, both boosting endothelial antithrombotic potential, could display a synergistic action in the treatment of thrombosis. Of the compounds 10a-h and 11a-d, shown to possess thrombin inhibitory activity, 11a-d were found to display radical scavenging activity, 10a, 10d, and 10f were demonstrated to inhibit lipid peroxidation of linoleic acid, and 10b and 10h inhibited soybean lipoxygenase. The observed combination of thrombin inhibition with lipid peroxidation and/or lipoxygenase inhibitory activity makes compounds 10 and 11 interesting candidates for further investigations towards multiple antithrombotic drugs. 相似文献
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123.
Kralj A Wetzel A Mahmoudian S Stamminger T Tschammer N Heinrich MR 《Bioorganic & medicinal chemistry letters》2011,21(18):5446-5450
The highly constitutively active G-protein coupled receptor US28 of human cytomegalovirus (HCMV) is an interesting pharmacological target because of its implication on viral dissemination, cardiovascular diseases and tumorigenesis. We found that dihydroisoquinolinone and tetrahydroisoquinoline scaffolds may be promising lead structures for novel US28 allosteric inverse agonists. These scaffolds were rapidly synthesized by radical carboamination reactions followed by non-radical transformations. Our novel US28 allosteric modulators provide valuable scaffolds for further ligand optimization and may be helpful chemical tools to investigate molecular mechanisms of US28 constitutive signaling and its role in pathogenesis. 相似文献
124.
The abilities of dihydrolipoic acid (DHLA) to scavenge peroxynitrite (ONOO?), galvinoxyl radical, 2,2′‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonate) cation radical (ABTS+?), and 2,2′‐diphenyl‐1‐picrylhydrazyl radical (DPPH) were higher than those of lipoic acid (LA). The effectiveness of DHLA to protect methyl linoleate against 2,2′‐azobis(2‐amidinopropane hydrochloride) (AAPH)‐induced oxidation was about 2.2‐fold higher than that of LA, and DHLA can retard the autoxidation of linoleic acid (LH) in the β‐carotene‐bleaching test. DHLA can also trap ~0.6 radicals in AAPH‐induced oxidation of LH. Moreover, DHLA can scavenge ~2.0 radicals in AAPH‐induced oxidation of DNA and AAPH‐induced hemolysis of erythrocytes, whereas LA can scavenge ~1.5 radicals at the same experimental conditions. DHLA can protect erythrocytes against hemin‐induced hemolysis, but accelerate the degradation of DNA in the presence of Cu2+. Therefore, the antioxidant capacity of –SH in DHLA is higher than S‐S in LA. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 25:216–223, 2011; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.20378 相似文献
125.
Bacterial resistance to 4,6-type aminoglycoside antibiotics, which target the ribosome, has been traced to the ArmA/RmtA family of rRNA methyltransferases. These plasmid-encoded enzymes transfer a methyl group from S-adenosyl-L-methionine to N7 of the buried G1405 in the aminoglycoside binding site of 16S rRNA of the 30S ribosomal subunit. ArmA methylates mature 30S subunits but not 16S rRNA, 50S, or 70S ribosomal subunits or isolated Helix 44 of the 30S subunit. To more fully characterize this family of enzymes, we have investigated the substrate requirements of ArmA and to a lesser extent its ortholog RmtA. We determined the Mg+2 dependence of ArmA activity toward the 30S ribosomal subunits and found that the enzyme recognizes both low Mg+2 (translationally inactive) and high Mg+2 (translationally active) forms of this substrate. We tested the effects of LiCl pretreatment of the 30S subunits, initiation factor 3 (IF3), and gentamicin/kasugamycin resistance methyltransferase (KsgA) on ArmA activity and determined whether in vivo derived pre-30S ribosomal subunits are ArmA methylation substrates. ArmA failed to methylate the 30S subunits generated from LiCl washes above 0.75 M, despite the apparent retention of ribosomal proteins and a fully mature 16S rRNA. From our experiments, we conclude that ArmA is most active toward the 30S ribosomal subunits that are at or very near full maturity, but that it can also recognize more than one form of the 30S subunit. 相似文献
126.
Martini M Gnann A Scheikl D Holzmann B Janssen KP 《The international journal of biochemistry & cell biology》2011,43(11):1630-1640
SASH1, a member of the SLY-family of signal adapter proteins, is a candidate tumor suppressor in breast and colon cancer. Reduced expression of SASH1 is correlated with aggressive tumor growth, metastasis formation, and inferior prognosis. However, the biological role of SASH1 remains largely unknown. To unravel the function of SASH1, we have analyzed the intracellular localization of endogenous SASH1, and have generated structural SASH1 mutants. SASH1 localized to the nucleus as well as to the cytoplasm in epithelial cells. In addition, SASH1 was enriched in lamellipodia and membrane ruffles, where it co-distributed with the actin cytoskeleton. Moreover, we demonstrate a novel interaction of SASH1 with the oncoprotein cortactin, a known regulator of actin polymerization in lamellipodia. Enhanced SASH1 expression significantly increased the content of filamentous actin, leading to the formation of cell protrusions and elongated cell shape. This activity was mapped to the central, evolutionarily conserved domain of SASH1. Furthermore, expression of SASH1 inhibited cell migration and lead to increased cell adhesion to fibronectin and laminin, whereas knock-down of endogenous SASH1 resulted in significantly reduced cell–matrix adhesion. Taken together, our findings unravel for the first time a mechanistic role for SASH1 in tumor formation by regulating the adhesive and migratory behaviour of cancer cells. 相似文献
127.
目的:探讨豚鼠支气管哮喘模型中共激活因子相关的精氨酸甲基转移酶1(coactivator-associated arginine methyltransferase1,CARM1)和核因子-B(NF-B)在气道和肺组织的表达变化及地塞米松的干预作用。方法:36只白色雄性豚鼠随机分为正常对照组、哮喘组和地塞米松治疗组。卵清蛋白致敏并激发后采用间接免疫荧光法检测气道和肺组织中CARM1和NF-B(P65)的表达,探讨其在哮喘中可能的作用机制。结果:CARM1和NF-κB(P65)在对照组、哮喘组及地塞米松治疗组均有阳性表达,主要在支气管-终末细支气管上皮细胞和肺组织细胞胞核表达。CARM1和NF-κB(P65)在哮喘组表达水平为([123.75±41.55)和(126.92±46.74)],在地塞米松治疗组表达水平为([84.33±27.70)和(85.00±29.22)],均高于对照组的([51.67±8.29)和(52.75±9.07)个/400倍视野],地塞米松治疗组表达较哮喘组低。结论:CARM1和NF-B(P65)在哮喘豚鼠气道上皮及肺组织细胞胞核高表达,提示CARM1可能通过增强募集NF-B到相关位点激活NF-B信号转导通路并启动了多种前炎性基因和免疫调节基因的转录激活、诱发哮喘炎症反应。地塞米松可下调CARM1和NF-κB的表达而抑制哮喘炎症反应。 相似文献
128.
Selenium uptake,translocation, assimilation and metabolic fate in plants 总被引:24,自引:0,他引:24
The chemical and physical resemblance between selenium (Se) and sulfur (S) establishes that both these elements share common
metabolic pathways in plants. The presence of isologous Se and S compounds indicates that these elements compete in biochemical
processes that affect uptake, translocation and assimilation throughout plant development. Yet, minor but crucial differences
in reactivity and other metabolic interactions infer that some biochemical processes involving Se may be excluded from those
relating to S. This review examines the current understanding of physiological and biochemical relationships between S and
Se metabolism by highlighting their similarities and differences in relation to uptake, transport and assimilation pathways
as observed in Se hyperaccumulator and non-accumulator plant species. The exploitation of genetic resources used in bioengineering
strategies of plants is illuminating the function of sulfate transporters and key enzymes of the S assimilatory pathway in
relation to Se accumulation and final metabolic fate. These strategies are providing the basic framework by which to resolve
questions relating to the essentiality of Se in plants and the mechanisms utilized by Se hyperaccumulators to circumvent toxicity.
In addition, such approaches may assist in the future application of genetically engineered Se accumulating plants for environmental
renewal and human health objectives. 相似文献
129.
130.