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81.
Lavanya Bondada Ramu Rondla Ugo Pradere Peng Liu Chengwei Li Drew Bobeck Tamara McBrayer Philip Tharnish Jerome Courcambeck Philippe Halfon Tony Whitaker Franck Amblard Steven J. Coats Raymond F. Schinazi 《Bioorganic & medicinal chemistry letters》2013,23(23):6325-6330
Herein, we report the synthesis and structure–activity relationship studies of new analogs of boceprevir 1 and telaprevir 2. Introduction of azetidine and spiroazetidines as a P2 substituent that replaced the pyrrolidine moiety of 1 and 2 led to the discovery of a potent hepatitis C protease inhibitor 37c (EC50 = 0.8 μM). 相似文献
82.
Xiaoke Guo Qian Yang Jing Xu Li Zhang Hongxi Chu Peng Yu Yingying Zhu Jinglian Wei Weilin Chen Yaozhong Zhang Xiaojin Zhang Haopeng Sun Yiqun Tang Qidong You 《Bioorganic & medicinal chemistry》2013,21(21):6466-6476
Atrial fibrillation (AF) is one of the common arrhythmias that threaten human health. Kv1.5 potassium channel is reported as an efficacious and safe target for the treatment of AF. In this paper, we designed and synthesized three series of compounds through modifying the lead compound RH01617 that was screened out by the pharmacophore model we reported earlier. All of the compounds were evaluated by the whole-patch lamp technology and most of them possessed potent inhibitory activities against Kv1.5. Compounds IIIi and IIIl were evaluated for the target selectivity as well as the pharmacodynamic effects in an isolated rat model. Due to the promising pharmacological behavior, compound IIIl deserves further pharmacodynamic and pharmacokinetic evaluations. 相似文献
83.
Zhao Peng Nao Shibata Hideaki Tada 《Bioscience, biotechnology, and biochemistry》2013,77(12):2094-2097
ABSTRACTCCR5-mediated cytotoxicity of staphylococcal bi-component toxins was investigated using human CCR5-expressing CHO cells. Cytotoxicity of rim domain loop-exchange mutants between LukE and Hlg2 indicated that loop-4 of LukE is essential for cytotoxicity in combination with LukD. Interestingly, Hlg2 showed LukF-dependent CCR5-mediated cytotoxicity, suggesting that the F-components of toxins also play a role in the cell-specific cytotoxicity. 相似文献
84.
Cancer cells have been found to express immunoglobulin G (IgG), but the exact functions and underlying mechanisms of cancer-derived IgG remain elusive. In this study, we first confirmed that downregulation of IgG restrained the growth and proliferation of cancer cells in vitro and in vivo. To elucidate its mechanism, we carried out a co-immunoprecipitation assay in HeLa cells and identified 27 potential IgG-interacting proteins. Among them, receptor of activated protein kinase C 1 (RACK1), ras-related nuclear protein (RAN) and peroxiredoxin 1 (PRDX1) are closely related to cell growth and oxidative stress, which prompted us to investigate the mechanism of action of IgG in the above phenomena. Upon confirmation of the interactions between IgG and the three proteins, further experiments revealed that downregulation of cancer-derived IgG lowered levels of intracellular reactive oxygen species (ROS) by enhancing cellular total antioxidant capacity. In addition, a few ROS scavengers, including catalase (CAT), dimethylsulfoxide (DMSO), n-acetylcysteine (NAC) and superoxide dismutase (SOD), further inhibited the growth of IgG-deficient cancer cells through suppressing mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) signaling pathway induced by a low level of intracellular ROS, whereas exogenous hydrogen peroxide (H2O2) at low concentration promoted their survival via increasing intracellular ROS levels. Similar results were obtained in an animal model and human tissues. Taken together, our results demonstrate that cancer-derived IgG can enhance the growth and proliferation of cancer cells via inducing the production of ROS at low level. These findings provide new clues for understanding tumor proliferation and designing cancer therapy. 相似文献
85.
86.
In this study, we prepared nano-hydroxyapatite/polyamide 66/glass fibre (n-HA/PA66/GF) bioactive bone screws. The microstructure, morphology and coating of the screws were characterised, and the adhesion, proliferation and viability of MC3T3-E1 cells on n-HA/PA66/GF scaffolds were determined using scanning electron microscope, CCK-8 assays and cellular immunofluorescence analysis. The results confirmed that n-HA/PA66/GF scaffolds were biocompatible and had no negative effect on MC3T3-E1 cells in vitro. To investigate the in vivo biocompatibility, internal fixation properties and osteogenesis of the bioactive screws, both n-HA/PA66/GF screws and metallic screws were used to repair intercondylar femur fractures in dogs. General photography, CT examination, micro-CT examination, histological staining and biomechanical assays were performed at 4, 8, 12 and 24 weeks after operation. The n-HA/PA66/GF screws exhibited good biocompatibility, high mechanical strength and extensive osteogenesis in the host bone. Moreover, 24 weeks after implantation, the maximum push-out load of the bioactive screws was greater than that of the metallic screws. As shown by their good cytocompatibility, excellent biomechanical strength and fast formation and ingrowth of new bone, n-HA/PA66/GF screws are thus suitable for orthopaedic clinical applications. 相似文献
87.
Yong Lian Jing Zhao Peiyu Xu Yimei Wang Jun Zhao Li Jia Ze Fu Li Jing Gang Liu Shuangqing Peng 《PloS one》2013,8(8)
Isoniazid (INH) and Rifampicin (RFP) are widely used in the world for the treatment of tuberculosis, but the hepatotoxicity is a major concern during clinical therapy. Previous studies showed that these drugs induced oxidative stress in liver, and several antioxidants abated this effect. Metallothionein (MT), a member of cysteine-rich protein, has been proposed as a potent antioxidant. This study attempts to determine whether endogenous expression of MT protects against INH and RFP-induced hepatic oxidative stress in mice. Wild type (MT+/+) and MT-null (MT−/−) mice were treated intragastrically with INH (150 mg/kg), RFP (300 mg/kg), or the combination (150 mg/kg INH +300 mg/kg RFP) for 21 days. The results showed that MT−/− mice were more sensitive than MT+/+ mice to INH and RFP-induced hepatic injuries as evidenced by hepatic histopathological alterations, increased serum AST levels and liver index, and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status. Furthermore, INH increased the protein expression of hepatic CYP2E1 and INH/RFP (alone or in combination) decreased the expression of hepatic CYP1A2. These findings clearly demonstrate that basal MT provides protection against INH and RFP-induced toxicity in hepatocytes. The CYP2E1 and CYP1A2 were involved in the pathogenesis of INH and RFP-induced hepatotoxicity. 相似文献
88.
Nan Jiang Cheng-he Qin Cai-xia Tan Shi-feng Wen Yun-fei Ma Fu Dong Xi-cai Diao Peng Zhang Bin Yu 《Cancer epidemiology》2013,37(3):294-299
Background: Update reports are rarely available regarding the bone giant cell tumors (GCTs) in the extremity in Chinese people. The aim of this study was to review the epidemiological characteristics of bone GCT in the extremity based on the clinical data from four hospitals in South China. Methods: We searched medical electronic records from January 2001 to December 2011 in four hospitals in South China to identify patients with definite diagnosis of extremity GCT. Epidemiological data including gender, tumor site, age at the time of first diagnosis, local recurrence and pulmonary metastasis were collected and analyzed statistically. Differences between-genders were particularly analyzed regarding first diagnosis age, tumor site, local recurrence and pulmonary metastasis. T-test and Chi-square test were used for continuous and dichotomous variables, respectively. Results: A total of 140 GCT patients (87 males and 53 females) were identified. The gender ratio was 1.64 for a male predominance. GCTs were mostly located around the knee (67 cases). 92 patients were in their 20s to 40s upon first diagnosis. The average age at the time of first diagnosis for all was 30.49 years, 30.76 years for males and 30.06 years for females (P = 0.757). GCT recurred locally in 50 patients (26 males and 24 females) with no gender difference (P = 0.065). The average interval from first surgery to local recurrence was 21.42 months. Pulmonary metastasis was found in 11 patients (8 males and 3 females) also with no gender difference (P = 0.667). The average interval from first diagnosis to metastasis was 36.45 months. Conclusions: Extremity GCT may have a male predominance in Chinese population and mostly occur at 20–40 years of age and around the knee. Follow-ups for GCT patients should be carried on for at least 3 years after primary surgery according to the average intervals for possible local recurrence and pulmonary metastasis. 相似文献
89.
Shuyan Ma Li Qing Xiaobo Yang Guiqiang Liang Li’e Zhang Qin Li Feng Xiong Suwan Peng Yifei Ma Xiaowei Huang Yunfeng Zou 《PloS one》2016,11(1)
Manganese (Mn) is an essential trace element, while excessive expose may induce neurotoxicity. Recently, lncRNAs have been extensively studied and it has been confirmed that lncRNAs participate in neural functions and aberrantly expressed lncRNAs are involved in neurological diseases. However, the pathological effects of lncRNAs on Mn-induced neurotoxicity remain unclear. In this study, the expression profiles of lncRNAs and messenger RNAs (mRNAs) were identified in Mn-treated hippocampal neurons and control neurons via microarray. Bioinformatic methods and intersection analysis were also employed. Results indicated that 566, 1161, and 1474 lncRNAs meanwhile 1848, 3228, and 4022 mRNAs were aberrantly expressed in low, intermediate, and high Mn-exposed groups compared with the control group, respectively. Go analysis determined that differentially expressed mRNAs were targeted to biological processes, cellular components, and molecular functions. Pathway analysis indicated that these mRNAs were enriched in insulin secretion, cell cycle, and DNA replication. Intersection analysis denominated that 135 lncRNAs and 373 mRNAs were consistently up-regulated while 150 lncRNAs and 560 mRNAs were consistently down-regulated. Meanwhile, lncRNA was significantly up-regulated while lncRNAs uc.229- and BC079195 were significantly down-regulated in three comparison groups. The relative expression levels of 3 lncRNAs and 4 mRNAs were validated through qRT-PCR. To the best of our knowledge, this study is the first to identify the expression patterns of lncRNAs and mRNAs in hippocampal neurons of Sprague–Dawley rats. The results may provide evidence on underlying mechanisms of Mn-induced neurotoxicity, and aberrantly expressed lncRNAs/mRNAs may be useful in further investigations to detect early symptoms of Mn-induced neuropsychiatric disorders in the central nervous system. BC089928相似文献
90.