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81.
Identification,Design and Bio-Evaluation of Novel Hsp90 Inhibitors by Ligand-Based Virtual Screening
JianMin Jia XiaoLi Xu Fang Liu XiaoKe Guo MingYe Zhang MengChen Lu LiLi Xu JinLian Wei Jia Zhu ShengLie Zhang ShengMiao Zhang HaoPeng Sun QiDong You 《PloS one》2013,8(4)
Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to virtually screen the SPECS databases, identifying 17 hits. Compound S1 and S13 exhibited the most potent inhibitory activity against Hsp90, with IC50 value 1.61±0.28 μM and 2.83±0.67 μM, respectively. Binding patterns analysis of the two compounds with Hsp90 revealed reasonable interaction modes. Further evaluation showed that the compounds exhibited good anti-proliferative effects against a series of cancer cell lines with high expression level of Hsp90. Meanwhile, S13 induced cell apoptosis in a dose-dependent manner in different cell lines. Based on the consideration of binding affinities, physicochemical properties and toxicities, 24 derivatives of S13 were designed, leading to the more promising compound S40, which deserves further optimization. 相似文献
82.
Hui Zhu Yugui Cui Jin Xie Ling Chen Xiangxiang Chen Xuejiang Guo Yefei Zhu Xinghai Wang Jiansun Tong Zuomin Zhou Yue Jia Yan‐he Lue Amiya Sinha Hikim Christina Wang Ronald S. Swerdloff Jiahao Sha 《Proteomics》2010,10(19):3480-3493
Mild testicular heating safely and reversibly suppresses spermatogenesis. In this study, we attempted to clarify the underlying molecular mechanism(s) involved in heat‐induced spermatogenesis suppression in human testis. We conducted global proteomic analyses of human testicular biopsies before, and at 2 and 9 wk after heat treatment. Thirty‐one and Twenty‐six known proteins were identified with significant differential expression at 2 and 9 wk after heat treatment, respectively. These were used to characterize the cellular and molecular events in the testes when seminiferous epithelia became damaged (2 wk) and recovered (9 wk). At 2 wk post‐treatment, the changed expression of a series of proteins could promote apoptosis or suppress proliferation and cell survival. At 9 wk post‐treatment, the changed expression of proteins mainly promoted cell proliferation, differentiation and survival, but resisted cell apoptosis. Among those heat‐regulated proteins, HNRNPH1 was selected for the further functional study. We found that HNRNPH1 was an anti‐apoptosis protein that could regulate the expression of other heat‐induced proteins. In conclusion, heat‐induced reversible suppression of spermatogenesis occurred by modulating the expression of proteins related to proliferation, differentiation, apoptosis and cell survival pathways. These differentially expressed proteins were found to be key molecular targets affecting spermatogenesis after heat treatment. 相似文献
83.
Xie L Lee SY Andersen JN Waters S Shen K Guo XL Moller NP Olefsky JM Lawrence DS Zhang ZY 《Biochemistry》2003,42(44):12792-12804
84.
Han Y Geng J Qiu Y Guo Z Zhou D Bi Y Du Z Song Y Wang X Tan Y Zhu Z Zhai J Yang R 《DNA and cell biology》2008,27(8):453-462
The catalase or catalase-peroxidase activity commonly exists in many pathogens and plays an important role in resisting the oxidative burst of phagocytes helping the pathogen persistently colonize in the host. Yersinia pestis is a facultative pathogen and the causative agent of plague. KatY has been identified as a thermosensing antigen with modest catalase activity in this pathogen. Here Y. pestis KatA and KatY were experimentally confirmed as a monofunctional catalase and bifunctional catalase-peroxidase, respectively. Their expression induced by H2O2 was proven to be mediated by the oxidative regulator, OxyR. Expression of KatA changed with growth phases and was crucial to its traditional physiological role in protecting Y. pestis cells against toxicity of exogenous H2O2. KatY was regulated by temperature and H2O2, two major elements of phagolysosomal microenvironments. Consistent with the above results, gene expression of katY increased significantly during intracellular growth of Y. pestis compared with that in vitro growth. However, a DeltakatY mutant was fully virulent to mice, suggesting that KatY is not required for Y. pestis virulence. 相似文献
85.
Both the Taihang Mountain area in north-central China and Chaoshan area in the southeastern littoral of China are areas with high risk of esophageal cancer (EC). Our previous study confirmed that populations from the two areas might share similar matrilineal backgrounds and found that mitochondrial DNA (mtDNA) haplogroup D, especially subhaplogroups D4a and D5a, might be genetic background markers of EC in Chaoshan area. Here, to further determine whether D4a, D5a, and D might be susceptibility markers for EC in the two high-risk areas, we performed a case–control study with larger samples and analyzed the distributions of these three haplogroups in subjects (controls [n = 898] and patients [n = 768]) from the two areas. D4a haplogroup was significantly associated with increased risk of EC in Taihang Mountain subjects, especially women. D5 haplogroup was associated with EC at the general population level in the Taihang Mountain area and in subjects ≤ 60 years, especially women ≤ 60 years, in the Chaoshan area. D haplogroup was associated with EC only in subjects ≤ 60 years, especially men ≤ 60 years, in the Chaoshan area. D4a and D5 showing positive association with EC in the Taihang Mountain area became the predominant subhaplogroups of D in Chaoshan controls. In conclusion, D, D4a, and D5 haplogroups might be susceptibility markers for EC in the two high-risk areas in China, particularly D4a and D5 for the Taihang Mountain area and D and D5 for the Chaoshan area. 相似文献
86.
87.
Dhillon B Badiwala MV Li SH Li RK Weisel RD Mickle DA Fedak PW Rao V Verma S 《Molecular and cellular biochemistry》2003,254(1-2):101-109
This report describes a novel ECTO-NOX protein with an oscillating activity having a period length of ca. 26 min encountered with buffy coat fractions and sera of aged individuals (70–100 years) that generates superoxide as measured by the reduction of ferricytochrome c. The oscillating, age-related reduction of ferricytochrome c is sensitive to superoxide dismutase, is inhibited by coenzyme Q and is reduced or absent from sera of younger individuals (20–40 years). An oscillating activity with a regular period length is a defining characteristic of ECTO-NOX proteins (a group of cell surface oxidases with enzymatic activities that oscillate). The period length of ca. 26 min is longer than the period length of 24 min for the usual constitutive (CNOX) ECTO-NOX proteins of the cell surface and sera which neither generate superoxide nor reduce ferricytochrome c. The aging-related ECTO-NOX protein (arNOX) provides a mechanism to transmit cell surface oxidative changes to surrounding cells and circulating lipoproteins potentially important to atherogenesis. Additionally, the findings provide a rational basis for the use of dietary coenzyme Q to retard aging-related arterial lesions. 相似文献
88.
89.
The use of transgenic livestock is providing new methods for obtaining pharmaceutically useful proteins. However, the protein expression profiles of the transgenic animals, including expression of milk fat globule membrane (MFGM) proteins, have not been well characterized. In this study, we compared the MFGM protein expression profile of the colostrum and mature milk from three lines of transgenic cloned (TC) cattle, i.e., expressing recombinant human α-lactalbumin (TC-LA), lactoferrin (TC-LF) or lysozyme (TC-LZ) in the mammary gland, with those from cloned non-transgenic (C) and conventionally bred normal animals (N). We identified 1, 225 proteins in milk MFGM, 166 of which were specifically expressed only in the TC-LA group, 265 only in the TC-LF group, and 184 only in the TC-LZ group. There were 43 proteins expressed only in the transgenic cloned animals, but the concentrations of these proteins were below the detection limit of silver staining. Functional analysis also showed that the 43 proteins had no obvious influence on the bovine mammary gland. Quantitative comparison revealed that MFGM proteins were up- or down-regulated more than twofold in the TC and C groups compared to N group: 126 in colostrum and 77 in mature milk of the TC-LA group; 157 in colostrum and 222 in mature milk of the TC-LF group; 49 in colostrum and 98 in mature milk of the TC-LZ group; 98 in colostrum and 132 in mature milk in the C group. These up- and down-regulated proteins in the transgenic animals were not associated with a particular biological function or pathway, which appears that expression of certain exogenous proteins has no general deleterious effects on the cattle mammary gland. 相似文献
90.
Aspland SE Ballatore C Castillo R Desharnais J Eustaquio T Goelet P Guo Z Li Q Nelson D Sun C Castellino AJ Newman MJ 《Bioorganic & medicinal chemistry letters》2006,16(19):5194-5198
In the present work, we explore the possibility of introducing selectivity to existing chemotherapeutics via the design of non-pro-drug, bi-functional molecules comprising a microtubule-binding agent and a substrate for a disease-associated kinase. The design, synthesis, and in vitro biological evaluation of paclitaxel-thymidine and vinblastine-thymidine bi-functional conjugates are reported here. This work provides the first account of 'kinase-mediated trapping' of cancer therapeutics. 相似文献