缺氧诱导因子1α与核因子κB在炎症缺氧环境中相互作用研究进展

慢性炎症是一系列临床难治疾病（包括心血管损伤、炎性肠病、癌症等）的病理学基础,而缺氧是慢性炎症引起组织损伤的重要病理生理学机制。缺氧诱导因子1α（hypoxia inducible factor-1α,HIF-1α）对组织适应缺氧具有调节作用。缺氧时,HIF-1α通过激活适应性转录反应以协调低氧组织中的氧供应和代谢活性,此过程涉及血管生成因子和血管活性物质等细胞因子的上调。调节免疫应答和细胞凋亡的核因子κB（nuclear factor-κB,NF-κB）具有与HIF-1α类似的功能,即在低氧条件下通过改变氧依赖性羟脯氨酸化酶活性来调节缺氧状态。此文讨论了在多种炎症性疾病中HIF-1α与NF-κB激活通路之间的相互作用,以及HIF-1α和NF-κB通路作为炎症性疾病治疗靶点的潜力。     

New anticancer strategies targeting HIF-1

Hypoxia-inducible factor-1 (HIF-1), which is present at high levels in human tumors, plays crucial roles in tumor promotion by up-regulating its target genes, which are involved in anaerobic energy metabolism, angiogenesis, cell survival, cell invasion, and drug resistance. Therefore, it is apparent that the inhibition of HIF-1 activity may be a strategy for treating cancer. Recently, many efforts to develop new HIF-1-targeting agents have been made by both academic and pharmaceutical industry laboratories. The future success of these efforts will be a new class of HIF-1-targeting anticancer agents, which would improve the prognoses of many cancer patients. This review focuses on the potential of HIF-1 as a target molecule for anticancer therapy, and on possible strategies to inhibit HIF-1 activity. In addition, we introduce YC-1 as a new anti-HIF-1, anticancer agent. Although YC-1 was originally developed as a potential therapeutic agent for thrombosis and hypertension, recent studies demonstrated that YC-1 suppressed HIF-1 activity and vascular endothelial growth factor expression in cancer cells. Moreover, it halted tumor growth in immunodeficient mice without serious toxicity during the treatment period. Thus, we propose that YC-1 is a good lead compound for the development of new anti-HIF-1, anticancer agents.     

Role of sirtuins and calorie restriction in neuroprotection: implications in Alzheimer's and Parkinson's diseases

Aging is the major known risk factor for the onset of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Mitochondria play a central role in aging as mitochondrial dysfunction increases with age and produces harmful levels of reactive oxygen species which leads to cellular oxidative stress (free-radical theory of aging). Oxidative stress is highly damaging to cellular macromolecules and is also a major cause of the loss and impairment of neurons in neurodegenerative disorders. A growing body of evidence suggests that modulation of sirtuin activity and restricting calorie intake has a strong neuroprotective effect. SIRT1 induction by the use of pharmacological activators or by calorie restriction (CR) diet regimen has been shown to protect against neuronal loss and impairment in the cellular and animal models of AD and PD. Here, we review the current knowledge and recent data related to the role of sirtuins and CR in neurodegeneration and discuss the potential underlying signaling pathways of neuroprotection that might serve as attractive targets for the future therapeutic intervention of these age-related neurodegenerative diseases.     

HIF SUMO化在高原低氧适应中的作用

低氧诱导因子-1是参与调节机体氧平衡的重要核转录因子。作为一种蛋白质,它的主要亚基HIF-1α受到多种翻译后的化学修饰,如泛素化、类泛素化等的影响,从而使其蛋白的稳定性、入核以及对下游基因的促转录活性受到调节。因此,研究HIF-1α翻译后的修饰,不仅有助于理解类似转录因子自身的调控,更能对HIF-1作为一个高原病的治疗靶标提供思路。