Late-onset Alzheimer＇s disease （LOAD） is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment...Late-onset Alzheimer＇s disease （LOAD） is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.展开更多
目的观察促心肌素(CT-1)C-末端肽在缺血再灌注损伤前后进行干预对大鼠心肌细胞凋亡的影响。方法制备心肌缺血再灌注损伤(MI/R)模型,27只SD大鼠随机分为正常组(N,n=5)、再灌注损伤模型组(D,n=6)、MI/R后CT-1干预组(T,n=8)和MI/R前CT-1干...目的观察促心肌素(CT-1)C-末端肽在缺血再灌注损伤前后进行干预对大鼠心肌细胞凋亡的影响。方法制备心肌缺血再灌注损伤(MI/R)模型,27只SD大鼠随机分为正常组(N,n=5)、再灌注损伤模型组(D,n=6)、MI/R后CT-1干预组(T,n=8)和MI/R前CT-1干预组(O,n=8)。检测各组血清肌酸激酶(CK)活性和丙二醛(MDA)浓度;并取缺血区及其周围心脏组织计算心肌细胞凋亡指数(AI)。结果 MI/R后,模型组SD大鼠的平均存活时间为(93.17±24.7)min,在MI/R前的CT-1干预组为(87.88±18.3)min,MI/R后的CT-1干预组为(155.5±80.13)min,明显长于模型组和MI/R前干预组(q值分别为3.171、3.716,P<0.01);模型组SD大鼠的血清CK、MDA浓度升高,梗死区周围的AI也升高(N vs D,q值分别为14.391、11.015、21.668,P<0.01);MI/R后CT-1干预组的大鼠,血清CK、MDA浓度及AI均有所降低(T vs D,q值分别为10.649、6.167、16.493,P<0.01),但仍高于正常组(q值分别为5.197、5.782、7.391,P<0.01);CT-1前干预组的动物,血清CK、MDA浓度明显高于模型组(q值分别为6.147、10.551,P<0.01),AI高于正常组(q=24.609,P<0.01),但与模型组比较无明显差异(q=1.683,P>0.05);心肌细胞的凋亡情况与心肌的损伤及氧化损伤程度,有明显的相关性(r值分别为0.9245、0.8679,P<0.01)。结论 CT-1 C-末端多肽再灌注早期短期使用能减轻心肌组织损伤及氧化损伤,以及心肌细胞凋亡的程度,使动物存活时间延长;但腹腔注射CT-1 C-末端多肽较长时间后,大鼠对MI/R的耐受力降低,组织损伤及氧化损伤的程度明显加重,且梗死周边区有相当的心肌细胞发生凋亡,动物的存活时间也较短。展开更多
基金supported by National Basic Research Development Program(973 Program)of China(2011CBA00400)the National Natural Science Foundation of China(91332201)+1 种基金the Natural Science Foundation of Shanghai Municipality,China(13JC1401500)the Fund for Medical Emerging Cutting-edge Technology of Shanghai Municipality,China(SHDC12012114)
文摘Late-onset Alzheimer＇s disease （LOAD） is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.
文摘目的观察促心肌素(CT-1)C-末端肽在缺血再灌注损伤前后进行干预对大鼠心肌细胞凋亡的影响。方法制备心肌缺血再灌注损伤(MI/R)模型,27只SD大鼠随机分为正常组(N,n=5)、再灌注损伤模型组(D,n=6)、MI/R后CT-1干预组(T,n=8)和MI/R前CT-1干预组(O,n=8)。检测各组血清肌酸激酶(CK)活性和丙二醛(MDA)浓度;并取缺血区及其周围心脏组织计算心肌细胞凋亡指数(AI)。结果 MI/R后,模型组SD大鼠的平均存活时间为(93.17±24.7)min,在MI/R前的CT-1干预组为(87.88±18.3)min,MI/R后的CT-1干预组为(155.5±80.13)min,明显长于模型组和MI/R前干预组(q值分别为3.171、3.716,P<0.01);模型组SD大鼠的血清CK、MDA浓度升高,梗死区周围的AI也升高(N vs D,q值分别为14.391、11.015、21.668,P<0.01);MI/R后CT-1干预组的大鼠,血清CK、MDA浓度及AI均有所降低(T vs D,q值分别为10.649、6.167、16.493,P<0.01),但仍高于正常组(q值分别为5.197、5.782、7.391,P<0.01);CT-1前干预组的动物,血清CK、MDA浓度明显高于模型组(q值分别为6.147、10.551,P<0.01),AI高于正常组(q=24.609,P<0.01),但与模型组比较无明显差异(q=1.683,P>0.05);心肌细胞的凋亡情况与心肌的损伤及氧化损伤程度,有明显的相关性(r值分别为0.9245、0.8679,P<0.01)。结论 CT-1 C-末端多肽再灌注早期短期使用能减轻心肌组织损伤及氧化损伤,以及心肌细胞凋亡的程度,使动物存活时间延长;但腹腔注射CT-1 C-末端多肽较长时间后,大鼠对MI/R的耐受力降低,组织损伤及氧化损伤的程度明显加重,且梗死周边区有相当的心肌细胞发生凋亡,动物的存活时间也较短。
