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Silvia Pastorekova Daniela Vullo Angela Casini Andrea Scozzafava Jaromir Pastorek Isao Nishimori 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):211-217
The tumor-associated transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isozymes IX (CA IX) and XII (CA XII) are involved in acidification of hypoxic tumors, a process correlated with poor prognosis and clinical outcome of patients harboring such tumors. This process may be reversed by inhibiting these enzymes with potent sulfonamide/sulfamate inhibitors. A series of such aromatic/heterocyclic sulfonamides incorporating 2,3,5,6-tetrafluorobenzoyl-, 2,3,5,6-tetrafluoro- phenylsulfonyl- and pentafluorophenylureido moieties has been investigated for its interaction with the catalytic domain of the human isozymes hCA IX and hCA XII. Some of these compounds showed excellent inhibitory properties against both isozymes IX and XII, with several subnanomolar inhibitors detected for the first time. These sulfonamides may constitute valuable candidates for the development of novel antitumor therapies based on the inhibition of such tumor-associated CA isozymes. 相似文献
33.
Wei Liu Yaoting Sun Weigang Ge Fangfei Zhang Lin Gan Yi Zhu Tiannan Guo Kexin Liu 《Molecular & cellular proteomics : MCP》2022,21(2):100187
Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia. To understand the underlying resistance mechanisms in response to imatinib mesylate (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for 2 months to generate derivative cells with mild, intermediate, and severe resistance to the drugs as defined by their increasing resistance index. PulseDIA-based (DIA [data-independent acquisition]) quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7082 proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin signaling pathway was found to be significantly enriched in both ADR-resistant and IMA-resistant K562 cells. In particular, isocitrate dehydrogenase (NADP(+)) 2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated isocitrate dehydrogenase (NADP(+)) 2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR. 相似文献
34.
钠离子通道阻断剂河鲀毒素(TTX)是致命的毒素之一,却是极具价值的神经生物学和生理学等生命科学研究领域的工具药.近年来,越来越多的研究指出,TTX具有强大的局部麻醉潜能,有望成为替代氨基酯类和氨基酰胺类局部麻醉药、避免阿片类药物滥用的新型麻醉药物.本文综述TTX局部麻醉应用的辅助药物、TTX缓释及控释给药系统等相关研究,旨在为局部麻醉新药研发提供参考并探讨新的思路. 相似文献
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Somayeh Najafi Dorcheh Soheila Rahgozar Daryush Talei 《Journal of cellular and molecular medicine》2021,25(13):6148-6160
Combination therapies, using medicinal herbs, are broadly recommended to attenuate the chemotherapy adverse effects. Based on our previous findings considering the anti-leukaemic effects of ginger extract on acute lymphoblastic leukaemia (ALL) cells, the present study was aimed to investigate the anti-cancer role of this pharmaceutical plant on ALL mice models. Moreover, we worked towards identifying the most anti-leukaemic derivative of ginger and the mechanism through which it may exert its cytotoxic impact. In vivo experiments were performed using five groups of six C57BL/6 nude mice, and the anti-leukaemic activity of ginger extract alone or in combination with methotrexate (MTX) was examined. Results showed increased survival rate and reduced damages in mice brain and liver tissues. Subsequently, MTT assay demonstrated synergistic growth inhibitory effect of 6-shogaol (6Sh) and MTX on ALL cell lines and patients primary cells. Eventually, the molecular anti-neoplastic mechanism of 6Sh was evaluated using Bioinformatics. Flow cytometry illustrated 6Sh-mediated apoptosis in Nalm-6 cells confirmed by Western blotting and RT-PCR assays. Further analyses exhibited the generation of reactive oxygen species (ROS) through 6Sh. The current study revealed the in vivo novel anti-leukaemic role of ginger extract, promoted by MTX. Moreover, 6-shogaol was introduced as the major player of ginger cytotoxicity through inducing p53 activity and ROS generation. 相似文献
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《Journal of biological dynamics》2013,7(2):645-662
Vancomycin-resistant enterococci (VRE) infections have been linked to increased mortality and costs. A new model of a VRE-infested intensive care unit (ICU) is introduced. It incorporates critical features including the difference between colonization and infection, the role of special preventive care treatment cycles, fitness cost, and antibiotic use. Five patient stages are considered: susceptible, colonized with and without special preventive care, and infected with and without treatment. Parameter ranges are determined representing different ICUs and incorporated to numerically simulate the model. Basic reproductive number of the infection is derived and the impacts of the parameters are analysed. Strategies to minimize VRE infections and outbreak risk are explored with a focus on efficient and simultaneous control of critical parameters. In particular, threshold values of the level of special preventive care and ICU compliance rate are given to achieve desired goals under various constraints. 相似文献
39.
《朊病毒》2013,7(3-4):234-244
ABSTRACTOne of the major medical challenges of the twenty-first century is the treatment of incurable and fatal neurodegenerative disorders caused by misfolded prion proteins. Since the discovery of these diseases a number of studies have been conducted to identify small molecules for their treatment, however to date no curative treatment is available. These studies can be highly expensive and time consuming, but more recent experimental approaches indicate a significant application for yeast prions in these studies. We therefore used yeast prions to optimize previous high-throughput methods for the cheaper, easier and more rapid screening of natural extracts. Through this approach we aimed to identify natural yeast-prion inhibitors that could be useful in the development of novel treatment strategies for neurodegenerative disorders. We screened 500 marine invertebrate extracts from temperate waters in Australia allowing the identification of yeast-prion inhibiting extracts. Through the bioassay-driven chemical investigation of an active Suberites sponge extract, a group of bromotyrosine derivatives were identified as potent yeast-prion inhibitors. This study outlines the importance of natural products and yeast prions as a first-stage screen for the identification of new chemically diverse and bioactive compounds. 相似文献
40.
The nucleoside antibiotic, 3′-azido-3′-deoxythymidine, or simply, azidothymidine has shown great promise in inhibiting the
human immuno deficiency virus and in reducing mortality among AIDS patients. Conformational properties of azidothymidine have
been investigated by quantum-mechanical PCILO method and compared with those of the parent nucleoside, thymidine. The results
indicate great similarity between them and this similarity is remarkably striking in the situations that prevail in aqueous
solution. This result has important biological significance in explaining the drug action of azidothymidine. 相似文献