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1.
The brain is very sensitive to changes in redox status; thus maintaining redox homeostasis in the brain is critical for the prevention of accumulating oxidative damage. Aging is the primary risk factor for developing neurodegenerative diseases. In addition to age, genetic and environmental risk factors have also been associated with disease development. The primary reactive insults associated with the aging process are a result of oxidative stress (OS) and nitrosative stress (NS). Markers of increased oxidative stress, protein and DNA modification, inflammation, and dysfunctional proteostasis have all been implicated in contributing to the progression of neurodegeneration. The ability of the cell to combat OS/NS and maintain a clearance mechanism for misfolded aggregating proteins determines whether or not it will survive. A critical pathway in this regard is the Nrf2 (nuclear factor erythroid 2-related factor 2)- antioxidant response element (ARE) pathway. Nrf2 activation has been shown to mitigate a number of pathologic mechanisms associated with Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis. This review will focus on the role of Nrf2 in these diseases and the potential for Nrf2 activation to attenuate disease progression. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2014,24(18):4523-4528
Osmolytes have been proposed as treatments for neurodegenerative proteinopathies including Alzheimer’s disease. However, for osmolytes to reach the clinic their efficacy must be improved. In this work, copper(I)-catalyzed azide–alkyne cycloaddition chemistry was used to synthesize glycoclusters bearing six copies of trehalose, lactose, galactose or glucose, with the aim of improving the potency of these osmolytes via multivalency. A trehalose glycocluster was found to be superior to monomeric trehalose in its ability to retard the formation of amyloid-beta peptide 40 (Aβ40) fibrils and protect neurons from Aβ40-induced cell death. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2019,29(15):1957-1961
In our efforts to further investigate the impact of the spacer and membrane anchor to the neuroprotective activities, a series of bivalent compounds that contain cholesterol and extended spacers were designed, synthesized and biologically characterized. Our results support previous studies that incorporation of a piperazine ring into the spacer significantly improved the protective potency of bivalent compounds in MC65 cell model. Spacer length beyond 21 atoms does not add further benefits with 21MO being the most potent one with an EC50 of 81.86 ± 11.91 nM. Our results also demonstrated that bivalent compound 21MO suppressed the production of mitochondria reactive oxygen species. Furthermore, our results confirmed that both of the spacer and membrane anchor moiety are essential to metal binding. Collectively, the results provide further evidence and information to guide optimization of such bivalent compounds as potential neuroprotectants for Alzheimer’s disease. 相似文献
4.
《Bioorganic & medicinal chemistry letters》2014,24(24):5805-5813
The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile. 相似文献
5.
In order to improve the conservation status of the Eld’s Deer (Cervus eldii), a critically endangered species in China, a population in a nature reserve on Hainan Island was studied. Abundances and behaviours in two different habitat types, natural and manipulated, were recorded. We found that different habitats were preferred according to season. Both sexes were more abundant in the manipulated habitat from January to May, with males being more abundant in the natural habitat from September to October. However, females, were significantly more abundant from April and May in the manipulated habitat. The deer preferred the more open manipulated habitat for feeding, consistent with greater food availability. This study provides useful evidence for managers to create seasonally suitable habitat for the conservation of this species on Hainan Island. Similar methods could also be applied to other deer species in China, most of which are facing critical survival challenges. 相似文献
6.
Peter V. Tishler 《The Yale journal of biology and medicine》2015,88(4):423-426
Many graduates of the Harvard Medical Unit (HMU) at Boston City Hospital, in either the clinical training/residency program or the research program at the Thorndike Memorial Laboratory, contributed in major ways to the HMU and constantly relived their HMU experiences. The HMU staff physicians, descending from founder and mentor physicians Francis W. Peabody, Soma Weiss, and George R. Minot, were dedicated to the teaching, development, and leadership of its clinical and research trainees, whose confidence and dedication to patient care as a result of their mentorship led many to lifelong achievements as clinicians, teachers, and mentors. Their experience also led to a lifelong love of the HMU (despite its loss), camaraderie, happiness, and intense friendships with their associates. 相似文献
7.
A series of thirty (30) thiazole analogs were prepared, characterized by 1H NMR, 13C NMR and EI-MS and evaluated for Acetylcholinesterase and butyrylcholinesterase inhibitory potential. All analogs exhibited varied butyrylcholinesterase inhibitory activity with IC50 value ranging between 1.59 ± 0.01 and 389.25 ± 1.75 μM when compared with the standard eserine (IC50, 0.85 ± 0.0001 μM). Analogs 15, 7, 12, 9, 14, 1, 30 with IC50 values 1.59 ± 0.01, 1.77 ± 0.01, 6.21 ± 0.01, 7.56 ± 0.01, 8.46 ± 0.01, 14.81 ± 0.32 and 16.54 ± 0.21 μM respectively showed excellent inhibitory potential. Seven analogs 15, 20, 19, 24, 28, 30 and 25 exhibited good acetylcholinesterase inhibitory potential with IC50 values 21.3 ± 0.50, 35.3 ± 0.64, 36.6 ± 0.70, 44.81 ± 0.81, 46.36 ± 0.84, 48.2 ± 0.06 and 48.72 ± 0.91 μM respectively. All other analogs also exhibited well to moderate enzyme inhibition. The binding mode of these compounds was confirmed through molecular docking. 相似文献
8.
A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer’s disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 μM and 0.0089 μM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 µM for hAChE; 0.101 µM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold. 相似文献
9.
城市化背景下人类与自然环境的矛盾呈现出多尺度、层级化特征,而传统生态网络的构建方式较少考虑不同尺度下生态要素的关系,无法从区域落实到中心城区,难以形成系统性的解决方案。研究在综合梳理各尺度生态网络构建方法的基础上,以长沙市为例,基于形态学空间格局分析(Morphological Spatial Pattern Analysis,MSPA)、景观连通性原理和生态斑块重要性评价识别生态源地,并通过多层级生态阻力面的确定,综合运用最小费用路径(Least-cost path method,LCP)、电路理论、层级传导理论、尺度嵌套等方法对市域、都市区、中心城区的生态网络进行了协同构建和层级优化,最后基于不同尺度生态网络的特点应用并落实到多层级的国土空间规划体系中。研究结果表明:(1)长沙市域生态网络和都市区生态网络具有较好的层级嵌套特征;共识别两尺度生态叠合源地14个、生态叠合廊道15条,主要通过中心城区内的湘江、浏阳河和捞刀河部分河段与外围生态绿圈相衔接,形成"外环内楔"的空间格局。(2)确定市域重要廊道、市域潜在廊道、生态叠合廊道、都市区重要廊道、都市区潜在廊道的核心保护面积共501.14 km2,并提取位于生态廊道核心保护区范围内的生态夹点和生态障碍点,以进一步落实生态保护修复策略。(3)得到具有重要生态连通功能的中心城区生态绿道长度441.2 km,生态修复单元56个,并结合生态阻力值划分为5级进行针对性修复。(4)基于不同尺度生态网络的衔接、嵌套,最终构建"市域总体生态安全格局-都市区城市生态空间发展格局-以城市绿道为基础的中心城区生态修复单元",并与不同层级的国土空间规划体系相对应。研究结果将为以大城市为中心的跨尺度生态系统修复和生态安全格局构建提供科学参考。 相似文献
10.