OBJECTIVE Lychee seed,a famous traditional Chinese medicine,recently were reported to improve the learning and memory abilities in mice.However,it is still unclear whether lychee seed saponins(LSS)can improve the cogn...OBJECTIVE Lychee seed,a famous traditional Chinese medicine,recently were reported to improve the learning and memory abilities in mice.However,it is still unclear whether lychee seed saponins(LSS)can improve the cognitive function and associated mechanisms.METHODS In present studies,we established the Alzheimer disease(AD)model by injecting Aβ25-35 into the lateral ventricle of rats.Then the spatial learning and memory abilities of LSS-treated rats were evaluated with the Morris water maze,meanwhile the protein expressions of AKT,GSK3β and Tau in the hippocampal neuron were analyzed by immunohistochemistry and Western blotting.RESULTS The results showed LSS can improve the cognitive functions of AD rats through shortening the escape latency,increasing the number across the platform,platform quadrant dwell time and the percentage of the total distance run platform quadrant.The protein expression of AKT was significantly up-regulated and that of GSK3β and Tau were decreased remarkably in the hippocampal CA1 area.CONCLUSION Our study is the first to show that LSS significantly improve the cognitive function and prevent hippocampal neuronal injury of the rats with AD by activation of the PI3K/AKT/GSK3βsignaling pathway,suggesting LSS may be developed into the nutrient supplement for the treatment of AD.展开更多
Currently, accumulating studies indicated that upregulation of glycogen synthase kinase-3β （GSK3β） played an important role in depression pathogenesis. Our previous study demonstrated that ammoxetine, a novel se- ...Currently, accumulating studies indicated that upregulation of glycogen synthase kinase-3β （GSK3β） played an important role in depression pathogenesis. Our previous study demonstrated that ammoxetine, a novel se- rotonin and norepinephrine uptake inhibitor, displayed antidepressant activity more potent and faster than existing antidepressants, which may be clue to the increasing of hippocampal inhibitory serine-phosphorylation of glycogen synthase kinase-3 （GSK3）. The present study was to evaluate whether activation of PI3K/Akt signaling, one of the most important pathways regulating the phosphorylation of GSK3β, was required for ammoxetine induced antide- pressant effects and upregulation of pGSK3β. Behavioral results indicated that acute oral administration of ammoxe- tine at 10 mg/kg produced robust antidepressant effects in the forced swimming test and learned helpless test in mice, which were blocked totally by phosphatidylinositol （PI3）-kinase （PI3K） inhibitor LY294002. Then, West- ern blot results demonstrated that ammoxetine induced increasing of GSK3 β phosphorylation and activation of PI3 K/ Akt signaling can also be antagonized at the same testing time points by LY294002. These findings suggest that ac- tivation of PI3 K/Akt/GSK3[3 signaling is pivotal and necessary for the antidepressant effects of ammoxetine in the forced swimming test and learned helpless test in mice.展开更多
磷脂酰肌醇3-激酶(PI3Ks)作为酪氨酸激酶和G蛋白偶联受体的主要下游分子,通过催化产生第二信使3,4,5-三磷酸磷脂酰肌醇(PIP3)并激活Akt、糖原合酶激酶-3(GSK-3)、Forkhead转录因子FoxO1、mTOR(mammalian target of rapamycin)等下游分子...磷脂酰肌醇3-激酶(PI3Ks)作为酪氨酸激酶和G蛋白偶联受体的主要下游分子,通过催化产生第二信使3,4,5-三磷酸磷脂酰肌醇(PIP3)并激活Akt、糖原合酶激酶-3(GSK-3)、Forkhead转录因子FoxO1、mTOR(mammalian target of rapamycin)等下游分子,将多种生长因子及细胞因子的信号传递到细胞内,从而对细胞增殖、分化、凋亡和葡萄糖转运等多种生物过程起重要的调节作用.PTEN(phosphatase and tensin homologue)是PI3K信号通路的重要负调节因子.本文将对PI3K-Akt信号通路在糖代谢中的作用予以简要综述.展开更多
OBJECTIVE Erzhi pills is a clas⁃sic prescription of Chinese medicine originated from Fu Shou Jing Fang in Ming dynasty,with the effects of nourishing kidney-Yin and hemosta⁃sis,black hair,strengthening muscles and bon...OBJECTIVE Erzhi pills is a clas⁃sic prescription of Chinese medicine originated from Fu Shou Jing Fang in Ming dynasty,with the effects of nourishing kidney-Yin and hemosta⁃sis,black hair,strengthening muscles and bones.As a classical prescription for nourishing kidney-Yin,Erzhi pills has been used to treat senile dementia in China for many years.Herein,our study aimed to investigate the protective effects of Erzhi pills in rat models of Alzheimer disease(AD)induced by ovariectomy as well as D-galactose and Aβ1-40 injection and to explore its potential mechanism.METHODS The model of AD rats was established by ovariectomy com⁃bined with D-galactose and Aβ1-40 injection.Ovariectomized rats were randomly divided into four groups:model group,estradiol valerate(0.80 mg·kg-1)group,Erzhi pills high(1.50 mg·kg-1)and low(0.75 mg·kg-1)doses group.In addition,rats of sham operation were selected as the sham operated group.Except for the sham oper⁃ated group,rats were injected intraperitoneally with D-galactose(100 mg·kg-1 per day,for 49 d)on the 8th day,then they were given intracerebro⁃ventricular injection of Aβ1-40(10μg per rat,1 g·L-1)on the 36th day,while the corresponding drugs were given by gastrointestinal administra⁃tion on the 22nd day.In our study,Morris water maze test was used to evaluate the learning and memory abilities,while ELISA kit was used to an⁃alyze serum estrogen level.The morphology of hippocampal neuron cells was observed by HE staining,and Nissl staining was utilized to ob⁃serve the Nissl body in cytoplasm.Then,the ex⁃pression of ERβpositive cells and hippocampal Aβ1-40 and p-Tau404 proteins was determined by immunohistochemistry.In order to further explore the molecular mechanism of Erzhi pills preven⁃tion and treatment of AD,proteomics was used to find potential targets and related pathways,Western blotting was used to verify the expres⁃sion of candidate differential protein.According to the results of proteomics in our experiment,Western blotting was used to detect the protein expression of PI3K,Akt,Bcl-2,Bcl-xl,Bad,14-3-3 and GSK3β.RESULTS The escape latency was significantly shortened,the number of crossing platform was increased,the neuron arrange⁃ment was more orderly and with less nuclear pycnosis in rats of Erzhi pills groups compared to the model group.In rats treated with Erzhi pills,the number of neurons,Nissl bodies,the estro⁃gen levels and ERβpositive cells were increased,while the number of Aβ1-40 and p-Tau404 positive cells was significantly decreased.Proteomics found that there were more than one hundred differentially expressed proteins of rats treated with Erzhi pills,which were involved in 48 signal⁃ing pathways.Among these proteins,five of them were involved in the PI3K/Akt signal path⁃way.As the down-stream protein of PI3K/Akt sig⁃naling pathway,the content of 14-3-3 protein was significantly increased.Western blotting analysis showed that the expression of p-GSK3β/GSK3βand Bad was decreased,while that of p-Akt/Akt,p-PI3K/PI3K,14-3-3,Bcl-xl and Bcl-2 was up-regulated in rats from the Erzhi pills groups compared with the model group.CON⁃CLUSION Erzhi pills can improve estrogen levels,alter proteomics expression of the hippocampus and activate PI3K/Akt pathway in AD rats,reduce Aβaggregation,inhibit the hyperphos⁃phorylation of Tau protein,maintain the morphol⁃ogy of hippocampal neurons and decrease the apoptosis of hippocampal neurons,thereby improving the learning and memory abilities of ovariectomized AD rats induced by D-galactose and Aβ1-40 injection.This study may provide an experimental basis for the clinical treatment of Erzhi pills.展开更多
基金supported by Science and Technology Planning Project of Sichuan Province(2008SZ0050,14JC0798)Educational Commission of Sichuan Province(10ZA035,15ZA0155)+1 种基金Science and Technology Program of Luzhou(2015-S-43,2016LZXNYD-T03)Key Development Program of Southwest Medical University(2010ZD-010)
文摘OBJECTIVE Lychee seed,a famous traditional Chinese medicine,recently were reported to improve the learning and memory abilities in mice.However,it is still unclear whether lychee seed saponins(LSS)can improve the cognitive function and associated mechanisms.METHODS In present studies,we established the Alzheimer disease(AD)model by injecting Aβ25-35 into the lateral ventricle of rats.Then the spatial learning and memory abilities of LSS-treated rats were evaluated with the Morris water maze,meanwhile the protein expressions of AKT,GSK3β and Tau in the hippocampal neuron were analyzed by immunohistochemistry and Western blotting.RESULTS The results showed LSS can improve the cognitive functions of AD rats through shortening the escape latency,increasing the number across the platform,platform quadrant dwell time and the percentage of the total distance run platform quadrant.The protein expression of AKT was significantly up-regulated and that of GSK3β and Tau were decreased remarkably in the hippocampal CA1 area.CONCLUSION Our study is the first to show that LSS significantly improve the cognitive function and prevent hippocampal neuronal injury of the rats with AD by activation of the PI3K/AKT/GSK3βsignaling pathway,suggesting LSS may be developed into the nutrient supplement for the treatment of AD.
文摘Currently, accumulating studies indicated that upregulation of glycogen synthase kinase-3β （GSK3β） played an important role in depression pathogenesis. Our previous study demonstrated that ammoxetine, a novel se- rotonin and norepinephrine uptake inhibitor, displayed antidepressant activity more potent and faster than existing antidepressants, which may be clue to the increasing of hippocampal inhibitory serine-phosphorylation of glycogen synthase kinase-3 （GSK3）. The present study was to evaluate whether activation of PI3K/Akt signaling, one of the most important pathways regulating the phosphorylation of GSK3β, was required for ammoxetine induced antide- pressant effects and upregulation of pGSK3β. Behavioral results indicated that acute oral administration of ammoxe- tine at 10 mg/kg produced robust antidepressant effects in the forced swimming test and learned helpless test in mice, which were blocked totally by phosphatidylinositol （PI3）-kinase （PI3K） inhibitor LY294002. Then, West- ern blot results demonstrated that ammoxetine induced increasing of GSK3 β phosphorylation and activation of PI3 K/ Akt signaling can also be antagonized at the same testing time points by LY294002. These findings suggest that ac- tivation of PI3 K/Akt/GSK3[3 signaling is pivotal and necessary for the antidepressant effects of ammoxetine in the forced swimming test and learned helpless test in mice.
文摘磷脂酰肌醇3-激酶(PI3Ks)作为酪氨酸激酶和G蛋白偶联受体的主要下游分子,通过催化产生第二信使3,4,5-三磷酸磷脂酰肌醇(PIP3)并激活Akt、糖原合酶激酶-3(GSK-3)、Forkhead转录因子FoxO1、mTOR(mammalian target of rapamycin)等下游分子,将多种生长因子及细胞因子的信号传递到细胞内,从而对细胞增殖、分化、凋亡和葡萄糖转运等多种生物过程起重要的调节作用.PTEN(phosphatase and tensin homologue)是PI3K信号通路的重要负调节因子.本文将对PI3K-Akt信号通路在糖代谢中的作用予以简要综述.
文摘OBJECTIVE Erzhi pills is a clas⁃sic prescription of Chinese medicine originated from Fu Shou Jing Fang in Ming dynasty,with the effects of nourishing kidney-Yin and hemosta⁃sis,black hair,strengthening muscles and bones.As a classical prescription for nourishing kidney-Yin,Erzhi pills has been used to treat senile dementia in China for many years.Herein,our study aimed to investigate the protective effects of Erzhi pills in rat models of Alzheimer disease(AD)induced by ovariectomy as well as D-galactose and Aβ1-40 injection and to explore its potential mechanism.METHODS The model of AD rats was established by ovariectomy com⁃bined with D-galactose and Aβ1-40 injection.Ovariectomized rats were randomly divided into four groups:model group,estradiol valerate(0.80 mg·kg-1)group,Erzhi pills high(1.50 mg·kg-1)and low(0.75 mg·kg-1)doses group.In addition,rats of sham operation were selected as the sham operated group.Except for the sham oper⁃ated group,rats were injected intraperitoneally with D-galactose(100 mg·kg-1 per day,for 49 d)on the 8th day,then they were given intracerebro⁃ventricular injection of Aβ1-40(10μg per rat,1 g·L-1)on the 36th day,while the corresponding drugs were given by gastrointestinal administra⁃tion on the 22nd day.In our study,Morris water maze test was used to evaluate the learning and memory abilities,while ELISA kit was used to an⁃alyze serum estrogen level.The morphology of hippocampal neuron cells was observed by HE staining,and Nissl staining was utilized to ob⁃serve the Nissl body in cytoplasm.Then,the ex⁃pression of ERβpositive cells and hippocampal Aβ1-40 and p-Tau404 proteins was determined by immunohistochemistry.In order to further explore the molecular mechanism of Erzhi pills preven⁃tion and treatment of AD,proteomics was used to find potential targets and related pathways,Western blotting was used to verify the expres⁃sion of candidate differential protein.According to the results of proteomics in our experiment,Western blotting was used to detect the protein expression of PI3K,Akt,Bcl-2,Bcl-xl,Bad,14-3-3 and GSK3β.RESULTS The escape latency was significantly shortened,the number of crossing platform was increased,the neuron arrange⁃ment was more orderly and with less nuclear pycnosis in rats of Erzhi pills groups compared to the model group.In rats treated with Erzhi pills,the number of neurons,Nissl bodies,the estro⁃gen levels and ERβpositive cells were increased,while the number of Aβ1-40 and p-Tau404 positive cells was significantly decreased.Proteomics found that there were more than one hundred differentially expressed proteins of rats treated with Erzhi pills,which were involved in 48 signal⁃ing pathways.Among these proteins,five of them were involved in the PI3K/Akt signal path⁃way.As the down-stream protein of PI3K/Akt sig⁃naling pathway,the content of 14-3-3 protein was significantly increased.Western blotting analysis showed that the expression of p-GSK3β/GSK3βand Bad was decreased,while that of p-Akt/Akt,p-PI3K/PI3K,14-3-3,Bcl-xl and Bcl-2 was up-regulated in rats from the Erzhi pills groups compared with the model group.CON⁃CLUSION Erzhi pills can improve estrogen levels,alter proteomics expression of the hippocampus and activate PI3K/Akt pathway in AD rats,reduce Aβaggregation,inhibit the hyperphos⁃phorylation of Tau protein,maintain the morphol⁃ogy of hippocampal neurons and decrease the apoptosis of hippocampal neurons,thereby improving the learning and memory abilities of ovariectomized AD rats induced by D-galactose and Aβ1-40 injection.This study may provide an experimental basis for the clinical treatment of Erzhi pills.
