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11.
Erawan Borkham-Kamphorst Eddy van de Leur Henning W. Zimmermann Karlin Raja Karlmark Lidia Tihaa Ute Haas Frank Tacke Thorsten Berger Tak W. Mak Ralf Weiskirchen 《生物化学与生物物理学报:疾病的分子基础》2013,1832(5):660-673
Lipocalin-2 is expressed under pernicious conditions such as intoxication, infection, inflammation and other forms of cellular stress. Experimental liver injury induces rapid and sustained LCN2 production by injured hepatocytes. However, the precise biological function of LCN2 in liver is still unknown. In this study, LCN2?/? mice were exposed to short term application of CCl4, lipopolysaccharide and Concanavalin A, or subjected to bile duct ligation. Subsequent injuries were assessed by liver function analysis, qRT-PCR for chemokine and cytokine expression, liver tissue Western blot, histology and TUNEL assay. Serum LCN2 levels from patients suffering from liver disease were assessed and evaluated. Acute CCl4 intoxication showed increased liver damage in LCN2?/? mice indicated by higher levels of aminotransferases, and increased expression of inflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α and MCP-1/CCL2, resulting in sustained activation of STAT1, STAT3 and JNK pathways. Hepatocytes of LCN2?/? mice showed lipid droplet accumulation and increased apoptosis. Hepatocyte apoptosis was confirmed in the Concanavalin A and lipopolysaccharide models. In chronic models (4 weeks bile duct ligation or 8 weeks CCl4 application), LCN2?/? mice showed slightly increased fibrosis compared to controls. Interestingly, serum LCN2 levels in diseased human livers were significantly higher compared to controls, but no differences were observed between cirrhotic and non-cirrhotic patients. Upregulation of LCN2 is a reliable indicator of liver damage and has significant hepato-protective effect in acute liver injury. LCN2 levels provide no correlation to the degree of liver fibrosis but show significant positive correlation to inflammation instead. 相似文献
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Angiogenesis is a key step for tumour growth and metastasis, and anti-angiogenesis has been proposed as an important strategy for cancer therapy. Tryptanthrin is a weakly basic alkaloid isolated from the dried roots of medicinal indigo plants and has been shown to possess anti-tumour activities on various cancer cell types. This study aims to investigate the in vitro and in vivo anti-angiogenic activities of tryptanthrin and to unravel its underlying molecular action mechanisms. Our results show that tryptanthrin inhibited the in vitro proliferation, migration, and tube formation of the human microvascular endothelial cells (HMEC-1) in a concentration-dependent manner and significantly suppressed angiogenesis in Matrigel plugs in mice. Mechanistic studies indicated that tryptanthrin reduced the expression of several pro-angiogenic factors (Ang-1, PDGFB and MMP2). Tryptanthrin was also found to suppress the VEGFR2-mediated ERK1/2 signalling pathway in HMEC-1 cells and molecular docking simulation indicated that tryptanthrin could bound to the ATP-binding site of VEGFR2. Collectively, the present study demonstrated that tryptanthrin exhibited both in vitro and in vivo anti-angiogenic activities by targeting the VEGFR2-mediated ERK1/2 signalling pathway and might have therapeutic potential for the treatment of angiogenesis-related diseases. 相似文献
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Timothy A. McCaffrey Constantine Tziros Jannet Lewis Richard Katz Robert Siegel William Weglicki Jay Kramer I. Tong Mak Ian Toma Liang Chen Elizabeth Benas Alexander Lowitt Shruti Rao Linda Witkin Yi Lian Yinglei Lai Zhaoqing Yang Sidney W. Fu 《International journal of biological sciences》2013,9(4):350-360
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Marie-Elodie Cattin Jessica Wang Jonathan J. Weldrick Cassandra L. Roeske Esther Mak Stephanie L. Thorn Jean N. DaSilva Yibin Wang Aldon J. Lusis Patrick G. Burgon 《The Journal of biological chemistry》2015,290(44):26699-26714
Aging and diseases generally result from tissue inability to maintain homeostasis through adaptation. The adult heart is particularly vulnerable to disequilibrium in homeostasis because its regenerative abilities are limited. Here, we report that MLIP (muscle enriched A-type lamin-interacting protein), a unique protein of unknown function, is required for proper cardiac adaptation. Mlip−/− mice exhibited normal cardiac function despite myocardial metabolic abnormalities and cardiac-specific overactivation of Akt/mTOR pathways. Cardiac-specific MLIP overexpression led to an inhibition of Akt/mTOR, providing evidence of a direct impact of MLIP on these key signaling pathways. Mlip−/− hearts showed an impaired capacity to adapt to stress (isoproterenol-induced hypertrophy), likely because of deregulated Akt/mTOR activity. Genome-wide association studies showed a genetic association between Mlip and early response to cardiac stress, supporting the role of MLIP in cardiac adaptation. Together, these results revealed that MLIP is required for normal myocardial adaptation to stress through integrated regulation of the Akt/mTOR pathways. 相似文献
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Chun C. Mak 《Molecular simulation》2015,41(1-3):156-167
Charge-transfer-to-solvent excited iodide–polar solvent molecule clusters, [I? (Solv)n]*, have attracted substantial interest over the past 20 years as they can undergo intriguing relaxation processes leading ultimately to the formation of gas-phase molecular analogues of the solvated electron. In this review article, we present a comprehensive overview of the development and application of state-of-the-art first-principles molecular dynamics simulation approaches to understand and interpret the results of femtosecond photoelectron spectroscopy experiments on [I? (Solv)n]* relaxation, which point to a high degree of solvent specificity in the electron solvation dynamics. The intricate molecular details of the [I? (Solv)n]* relaxation process are presented, and by contrasting the relaxation mechanisms of clusters with several different solvents (water, methanol and acetonitrile), the molecular basis of the solvent specificity of electron solvation in [I? (Solv)n]* is uncovered, leading to a more refined view of the manifestation of electron solvation in small gas-phase clusters. 相似文献
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Jie Yu Jiacheng Zheng Jiajia Lin Linlu Jin Rui Yu Shinghung Mak Shengquan Hu Hongya Sun Xiang Wu Zaijun Zhang Mingyuen Lee Wahkeung Tsim Wei Su Wenhua Zhou Wei Cui Yifan Han Qinwen Wang 《Cellular and molecular neurobiology》2017,37(4):655-664
Oxidative stress-induced neuronal apoptosis plays an important role in many neurodegenerative disorders. In this study, we have shown that indirubin-3-oxime, a derivative of indirubin originally designed for leukemia therapy, could prevent hydrogen peroxide (H2O2)-induced apoptosis in both SH-SY5Y cells and primary cerebellar granule neurons. H2O2 exposure led to the increased activities of glycogen synthase kinase 3β (GSK3β) and extracellular signal-regulated kinase (ERK) in SH-SY5Y cells. Indirubin-3-oxime treatment significantly reversed the altered activity of both the PI3-K/Akt/GSK3β cascade and the ERK pathway induced by H2O2. In addition, both GSK3β and mitogen-activated protein kinase inhibitors significantly prevented H2O2-induced neuronal apoptosis. Moreover, specific inhibitors of the phosphoinositide 3-kinase (PI3-K) abolished the neuroprotective effects of indirubin-3-oxime against H2O2-induced neuronal apoptosis. These results strongly suggest that indirubin-3-oxime prevents H2O2-induced apoptosis via concurrent inhibiting GSK3β and the ERK pathway in SH-SY5Y cells, providing support for the use of indirubin-3-oxime to treat neurodegenerative disorders caused or exacerbated by oxidative stress. 相似文献
20.
目的:研究电流耦合型人体通信(Intra-Body Communication,IBC)的传输特性.方法:以人体通信中最常使用到的部位-人体手臂为着眼点,合理抽象并得到手臂的等效数学模型,进而使用有限元方法探究人体中电流分布机理.另外,通过给模型施加不同形式下电信号,比较分析人体的信道特性.结果:①在安全阚值内,注入人体电流大小对信号衰减影响不大;②信号衰减随着发送电极尺寸的增大而减小:③收发电极间距离愈大,信号衰减愈大;④人体通信电流主要流经肌肉层,不过随频率增大,集肤效应明显,在骨中的比例很小,足以忽略.结论:本文提出的人体手臂等效有限元模型,可以对电流耦合型人体通信的通信机理展开分析. 相似文献