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31.
Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.  相似文献   
32.
Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.  相似文献   
33.
Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the population over the age of 60. Diabetes Mellitus (DM) is a metabolic disorder that affects approximately 25% of adults over the age of 60. Recent studies showed that DM increases the risk of developing PD. The link between DM and PD has been discussed in the literature in relation to different mechanisms including mitochondrial dysfunction, oxidative stress, and protein aggregation. In this paper, we review the common microRNA (miRNA) biomarkers of both diseases. miRNAs play an important role in cell differentiation, development, the regulation of the cell cycle, and apoptosis. They are also involved in the pathology of many diseases. miRNAs can mediate the insulin pathway and glucose absorption. miRNAs can also regulate PD-related genes. Therefore, exploring the common miRNA biomarkers of both PD and DM can shed a light on how these two diseases are correlated, and targeting miRNAs is a potential therapeutic opportunity for both diseases.  相似文献   
34.
A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the absorption of heparin after oral administration, in which heparin was compounded with phospholipids to achieve better fat solubility in the form of heparin-phospholipid (HEP-Pc) complex. HEP-Pc complex was prepared using the solvent evaporation method, which increased the solubility of heparin in n-octanol. The successful preparation of HEP-Pc complex was confirmed by differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR) spectroscopy, NMR, and SEM. A heparin lipid microemulsion (HEP-LM) was prepared by high-pressure homogenization and characterized. HEP-LM can enhance the absorption of heparin after oral administration, significantly prolong activated partial thromboplastin time (APTT) and thrombin time (TT) in mice, and reduce fibrinogen (FIB) content. All these outcomes indicate that HEP-LM has great potential as an oral heparin formulation.  相似文献   
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海胆酮是一种酮式类胡萝卜素,主要从海胆及藻类等海洋生物中提取。本文研究海胆酮对乙酰胆碱酯酶(acetylcholinesterase,AChE)的抑制作用,应用酶动力学、荧光光谱、圆二色光谱和分子对接技术研究海胆酮对AChE的抑制机理,并用淀粉样β蛋白片段25~35(amyloid beta-peptide 25-35,Aβ25-35)诱导大鼠肾上腺嗜铬细胞瘤细胞(PC12细胞)建立阿尔茨海默症(Alzheimer’s disease,AD)模型,研究海胆酮对AD细胞模型氧化应激损伤的作用。结果表明,海胆酮有很强的AChE抑制活性,其半抑制质量浓度为(16.29±0.97)μg/mL,抑制常数Ki为3.82 μg/mL,表现为竞争性抑制;海胆酮可诱导AChE二级结构改变,更容易与AChE活性中心氨基酸Ser200、His440、Trp84和Tyr121结合,阻碍底物碘代硫代乙酰胆碱(acetylthiocholine iodide,ATCI)与酶结合,从而引起酶活力降低。海胆酮能有效抑制Aβ25-35诱导PC12细胞的AChE活力,降低丙二醛含量,增加超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶活力,减轻Aβ25-35诱导的PC12细胞氧化应激损伤。本研究基于AChE和氧化应激阐明了海胆酮对AD的潜在作用机制,为海胆酮在功能食品、生物医药等领域的应用提供了数据支持和理论根据。  相似文献   
39.
杨春燕  宾冬梅  黎新 《电信科学》2021,37(2):144-153
提出了一种基于实用拜占庭容错(PBFT)算法的区块链技术,首先对传统的实用拜占庭容错算法原理进行了阐述,该传统算法包含前期、需求、预准备、准备、确认、答复6个阶段,但传统算法具有实时性差、缺乏惩罚机制、带宽高的缺点。针对出现的这些问题,又对传统算法进行了改进,具体涉及记账节点、共识过程以及视图切换过程。通过测试进一步证明了该改进算法的实用性,并将该算法应用于电网企业中,构建的虚拟仓库实现了联储联备,降低了库存资金的耗费,并且提高了电网企业库存管理的效率。  相似文献   
40.
为了充分挖掘多能源之间的互补潜力,使工业园区混合能源系统的配置方式由传统粗放式转变为精确优化配置并降低系统配置方案的保守性,基于粒子群联合CPLEX求解算法对工业园区的系统配置和运行调度方案进行分析优化,并以某生物园区为例进行了实例分析,得到了目标函数下的最优设计方案和运行策略。仿真分析结果表明,优化配置方法的应用能够协调冷热电多种能源的混合利用,提升系统的综合经济性。同时,为工业园区能源供应项目的规划、设计提供参考性支撑,丰富设计手段。  相似文献   
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