In the present study,Fmr1 knockout mice （KO mice） were used as the model for fragile X syndrome.The results of step-through and step-down tests demonstrated that Fmr1 KO mice had shorter latencies and more error cou...In the present study,Fmr1 knockout mice （KO mice） were used as the model for fragile X syndrome.The results of step-through and step-down tests demonstrated that Fmr1 KO mice had shorter latencies and more error counts,indicating a learning and memory disorder.After treatment with 30,60,90,120,or 200 mg/kg lithium chloride,the learning and memory abilities of the Fmr1 KO mice were significantly ameliorated,in particular,the 200 mg/kg lithium chloride treatment had the most significant effect.Western blot analysis showed that lithium chloride significantly enhanced the expression of phosphorylated glycogen synthase kinase 3 beta,an inactive form of glycogen synthase kinase 3 beta,in the cerebral cortex and hippocampus of the Fmr1 KO mice.These results indicated that lithium chloride improved learning and memory in the Fmr1 KO mice,possibly by inhibiting glycogen synthase kinase 3 beta activity.展开更多
1-methyl-4-phenylpyridinium ion （MPP^＋） induces endoplasmic reticulum stress and activates caspase-12 in PC12 cells, leading to neuronal apoptosis. However, the underlying molecular mechanism remains unknown. The p...1-methyl-4-phenylpyridinium ion （MPP^＋） induces endoplasmic reticulum stress and activates caspase-12 in PC12 cells, leading to neuronal apoptosis. However, the underlying molecular mechanism remains unknown. The present study investigated the regulatory effects of nerve growth factor （Akt activator） and lithium chloride （glycogen synthase kinase-3β inhibitor） on the endoplasmic reticulum stress signaling pathway. The results revealed that MPP＋ induced expression of Bip and C/EBP homologous protein. The upregulation of Bip and C/EBP homologous protein, as well as the decreased pro-caspase-12 level induced by MPP^＋ were inhibited by pretreatment of the nerve growth factor or lithium chloride. These results suggest that the phosphatidylinositol 3 kinase-Aktglycogen synthase kinase-3β pathway is involved in MPP-induced endoplasmic reticulum stress.展开更多
Alzheimer’s disease (AD) is the most prevalent cause of dementia worldwide. Because of the progressive neurodegeneration, individual cognitive and behavioral functions are impaired, affecting the quality of life of m...Alzheimer’s disease (AD) is the most prevalent cause of dementia worldwide. Because of the progressive neurodegeneration, individual cognitive and behavioral functions are impaired, affecting the quality of life of millions of people. Although the exact pathogenesis of AD has not been fully elucidated, amyloid plaques, neurofibrillary tangles (NFTs), and sustaining neuroinflammation dominate its characteristics. As one of the major tau kinases leading to hyperphosphorylation and aggregation of tau, glycogen synthase kinase-3β (GSK-3β) has been drawing great attention in various AD studies. Another research focus of AD in recent years is the inflammasome, a multiprotein complex acting as a regulator in immunological reactions to exogenous and endogenous danger signals, of which the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome has been studied mostly in AD and proven to play a significant role in AD development by its activation and downstream effects such as caspase-1 maturation and interleukin (IL)-1β release. Studies have shown that the NLRP3 inflammasome is activated in a GSK-3β-dependent way and that inhibition of the NLRP3 inflammasome downregulates GSK-3β, suggesting that these two important proteins are closely related. This article reviews the respective roles of GSK-3β and the NLRP3 inflammasome in AD as well as their relationship and interaction.展开更多
Tau oligomers are the etiologic molecules of Alzheimer disease(AD), and correlate strongly with neuronal loss and exhibit neurotoxicity. Recent evidence indicates that small tau oligomers are the most relevant toxic a...Tau oligomers are the etiologic molecules of Alzheimer disease(AD), and correlate strongly with neuronal loss and exhibit neurotoxicity. Recent evidence indicates that small tau oligomers are the most relevant toxic aggregate species. The aim of the present study was to investigate the mechanisms of cornel iridoid glycoside(CIG) on tau oligomers and cognitive functions. We injected wortmannin and GF-109203 X(WM/GFX, 200 μmol·L-1 each) into the lateral ventricles to induce tau oligomer and memory impairment in rats. When oral y administered with CIG at 60 and 120 mg·kg-1 per day for 14 d, CIG decreased the escape latency in Morris water maze test. We also found that CIG restored the expression of presynaptic p-synapsin, synaptophysin, and postsynaptic density-95(PSD-95) decreased by WM/GFX in rat cortex. CIG reduced the accumulation of tau oligomers in the brain of WM/GFX rats and in cells transfected with wild type glycogen synthase kinase-3β(wt GSK-3β). In addition, CIG up-regulated the levels of ATG7, ATG12, Beclin-1, and LC3 II in vivo and in vitro, suggesting the restoration of autophagy function. These results suggest that CIG could ameliorate memory deficits and regulate memory-associated synaptic proteins through the clearance of tau oligomers accumulation. Moreover, CIG clears tau oligomers by restoring autophagy function.展开更多
Interleukin-4(IL-4) has a protective effect against cerebral ischemia/reperfusion injury. Animal experiments have shown that IL-4 improves the short-and long-term prognosis of neurological function. The Akt(also calle...Interleukin-4(IL-4) has a protective effect against cerebral ischemia/reperfusion injury. Animal experiments have shown that IL-4 improves the short-and long-term prognosis of neurological function. The Akt(also called protein kinase B, PKB)/glycogen synthase kinase-3β(Akt/GSK-3β) signaling pathway is involved in oxidative stress, the inflammatory response, apoptosis, and autophagy. However, it is not yet clear whether the Akt/GSK-3β pathway participates in the neuroprotective effect of IL-4 against cerebral ischemia/reperfusion injury. In the present study, we established a cerebral ischemia/reperfusion mouse model by middle cerebral artery occlusion for 60 minutes followed by a 24-hour reperfusion. An IL-4/anti-IL-4 complex(10 μg) was intraperitoneally administered 30 minutes before surgery. We found that administration of IL-4 significantly alleviated the neurological deficits, oxidative stress, cell apoptosis, and autophagy and reduced infarct volume of the mice with cerebral ischemia/reperfusion injury 24 hours after reperfusion. Simultaneously, IL-4 activated Akt/GSK-3β signaling pathway. However, an Akt inhibitor LY294002, which was injected at 15 nmol/kg via the tail vein, attenuated the protective effects of IL-4. These findings indicate that IL-4 has a protective effect on cerebral ischemia/reperfusion injury by mitigating oxidative stress, reducing apoptosis, and inhibiting excessive autophagy, and that this mechanism may be related to activation of the Akt/GSK-3β pathway. This animal study was approved by the Animal Ethics Committee of Renmin Hospital of Wuhan University, China(approval No. WDRY2017-K037) on March 9, 2017.展开更多
The present study established global brain ischemia using the four-vessel occlusion method. Following three rounds of reperfusion for 30 seconds, and occlusion for 10 seconds, followed by reperfusion for 48 hours, inf...The present study established global brain ischemia using the four-vessel occlusion method. Following three rounds of reperfusion for 30 seconds, and occlusion for 10 seconds, followed by reperfusion for 48 hours, infarct area, the number of TUNEL-positive cells and Bcl-2 expression were significantly reduced. However, glycogen synthase kinase-3β activity, cortical Bax and caspase-3 expression significantly increased, similar to results following ischemic postconditioning. Our results indicated that ischemic postconditioning may enhance glycogen synthase kinase-3β activity, a downstream molecule of the phosphatase and tensin homolog deleted on chromosome 10/phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which reduces caspase-3 expression to protect the brain against ischemic injury.展开更多
Myocardial ischemia/reperfusion injury can lead to severe brain injury.Glycogen synthase kinase 3 beta is known to be involved in myocardial ischemia/reperfusion injury and diabetes mellitus.However,the precise role o...Myocardial ischemia/reperfusion injury can lead to severe brain injury.Glycogen synthase kinase 3 beta is known to be involved in myocardial ischemia/reperfusion injury and diabetes mellitus.However,the precise role of glycogen synthase kinase 3 beta in myocardial ischemia/reperfusion injury-induced brain injury is unclear.In this study,we observed the effects of glycogen synthase kinase 3 beta on brain injury induced by myocardial ischemia/reperfusion injury in diabetic rats.Rat models of diabetes mellitus were generated via intraperitoneal injection of streptozotocin.Models of myocardial ischemia/reperfusion injury were generated by occluding the anterior descending branch of the left coronary artery.Post-conditioning comprised three cycles of ischemia/reperfusion.Immunohistochemical staining and western blot assays demonstrated that after 48 hours of reperfusion,the structure of the brain was seriously damaged in the experimental rats compared with normal controls.Expression of Bax,interleukin-6,interleukin-8,terminal deoxynucleotidyl transferase d UTP nick end labeling,and cleaved caspase-3 in the brain was significantly increased,while expression of Bcl-2,interleukin-10,and phospho-glycogen synthase kinase 3 beta was decreased.Diabetes mellitus can aggravate inflammatory reactions and apoptosis.Ischemic post-conditioning with glycogen synthase kinase 3 beta inhibitor lithium chloride can effectively reverse these changes.Our results showed that myocardial ischemic post-conditioning attenuated myocardial ischemia/reperfusion injury-induced brain injury by activating glycogen synthase kinase 3 beta.According to these results,glycogen synthase kinase 3 beta appears to be an important factor in brain injury induced by myocardial ischemia/reperfusion injury.展开更多
Multiple roles of glycogen synthase kinase-3（GSK-3）in neural tissues：GSK-3 is a serine/threonine kinase that has two isoforms encoded by two different genes,GSK-3αand GSK-3β,in mammals.GSK-3 has several sites of ...Multiple roles of glycogen synthase kinase-3（GSK-3）in neural tissues：GSK-3 is a serine/threonine kinase that has two isoforms encoded by two different genes,GSK-3αand GSK-3β,in mammals.GSK-3 has several sites of serine and tyrosine phosphorylation.展开更多
Background： Cognitive impairment is a severe complication caused by obstructive sleep apnea （OSA）. The mechanisms of causation are still unclear. The Wntβ-catenin signaling pathway is involved in cognition, and ab...Background： Cognitive impairment is a severe complication caused by obstructive sleep apnea （OSA）. The mechanisms of causation are still unclear. The Wntβ-catenin signaling pathway is involved in cognition, and abnormalities in it are implicated in neurological disorders. Here, we explored the Wntβ-catenin signaling pathway abnormalities caused by chronic intermittent hypoxia （CIH）, the most characteristic pathophysiological component of OSA. Methods： We divided 32 4-week-old male C57/BL mice into four groups of eight each： a CIH ＋ normal saline （NS） group, CIH ＋ LiCI group, sham CIH ＋ NS group, and a sham CIH ＋ LiCI group. The spatial learning performance of each group was assessed by using the Morris water maze （MWM）. Protein expressions of glycogen synthase kinase-β （GSK-β） and β-catenin in the hippocampus were examined using the Western blotting test. EdU labeling and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining methods were used, respectively, to determine the proliferation and apoptosis of neurons in the hippocampal dentate gyrus region. Results： Mice exposed to CIH showed impaired spatial learning performance in the MWM, including increased mean escape latencies to reach the target platform, decreased mean times passing through the target platform and mean duration in the target quadrant. The GSK-313 activity increased, and expression of β-catenin decreased significantly in the hippocampus of the CIH-exposed mice. Besides, CIH significantly increased hippocampal neuronal apoptosis, with an elevated apoptosis index. Meanwhile, LiCI decreased the activity of GSK-β and increased the expression of β-catenin and partially reversed the spatial memory deficits in MWM and the apoptosis caused by CIH. Conclusions： Wntβ-catenin signaling pathway abnormalities possibly play an important role in the development of cognitive deficits among mice exposed to CIH and that LiCI might attenuate CIH-induced cognitive impairment via Wntβ-catenin signaling pathway.展开更多
Insulin resistance is the pathophysiological basis of many diseases.Overcoming early insulin resistance highly significant in prevention diabetes,non-alcoholic fatty liver,and atherosclerosis.The present study aimed a...Insulin resistance is the pathophysiological basis of many diseases.Overcoming early insulin resistance highly significant in prevention diabetes,non-alcoholic fatty liver,and atherosclerosis.The present study aimed at evaluating the therapeutic effects of baicalin on insulin resistance and skeletal muscle ectopic fat storage in high fat diet-induced mice,and exploring the potential molecular mechanisms.Insulin resistance in mice was induced with a high fat diet for 16 weeks.Animals were then treated with three different doses of baicalin(100,200,and 400 mg·kg^(-1)·d^(-1)for 14 weeks.Fasting blood glucose,fasting serum insulin,glucose tolerance test(GTT),insulin tolerance test(ITT),and skeletal muscle lipid deposition were measured.Additionally,the AMP-activated protein kinase/acetyl-CoA carboxylase and protein kinase B/Glycogen synthase kinase 3 beta pathways in skeletal muscle were further evaluated.Baicalin significantly reduced the levels of fasting blood glucose and fasting serum insulin and attenuated high fat diet induced glucose tolerance and insulin tolerance.Moreover,insulin resistance was significantly reversed.Pathological analysis revealed baicalin dose-dependently decreased the degree of the ectopic fat storage in skeletal muscle.The properties of baicalin were mediated,at least in part,by inhibition of the AMPK/ACC pathway,a key regulator of de novo lipogenesis and activation of the Akt/GSK-3β pathway,a key regulator of Glycogen synthesis.These data suggest that baicalin,at dose up to 400 mg·kg^(-1)·d^(-1),is safe and able to attenuate insulin resistance and skeletal muscle ectopic fat storage,through modulating the skeletal muscle AMPK/ACC pathway and Akt/GSK-3β pathway.展开更多
Background Diabetes-related pathogenic factors can cause retinal ganglion cell （RGC） apoptosis, but the specific mechanism is not very clear. The aim of this study is to investigate the correlation between glycogen ...Background Diabetes-related pathogenic factors can cause retinal ganglion cell （RGC） apoptosis, but the specific mechanism is not very clear. The aim of this study is to investigate the correlation between glycogen synthase kinase-3 （GSK-3） activation and retinal neuron apoptosis. Methods In an in vitro experiment, the number of apoptotic RGC-5 cells differentiated by staurosporine was evaluated via flow cytometry and nuclei staining using Hoechst 33258. GSK-3 phosphorylation and caspase-3 activation in RGC-5 cells after serum deprivation were determined using Western blotting. Mitochondrial membrane potential was detected using the dye 5,5＇,6,6＇-tetrachloro-l,l＇,3,3＇-tetrethyl benzimidalyl carbocyanine iodide, and reactive oxygen species （ROS） levels were measured with dihydroethidium. In an in vivo experiment, the number of apoptotic retinal neurons was evaluated via terminal transferase dUTP nick-end labeling （TUNEL）, and GSK-3 phosphorylation was determined using Western blotting, in the retinal nerve epithelial tissue of rats in which diabetes was induced by intravenous tail-vein injection of streptozotocin for 4 weeks. Results The levels of phosphorylated Ser21/9 in GSK-3α/13 and p-T308/S473-AKT were lower and the cleaved caspase-3 levels were higher in the serum-deprived model （P 〈0.05）. Lithium chloride treatment was associated with a slower rate of apoptosis, increased mitochondrial membrane potential, and decreased ROS levels in differentiated RGC-5 cells （P 〈0.05）. The level of blood glucose and the number of TUNEL-positive cells in the whole-mounted retinas were higher （P 〈0.01）, and the levels of phosphorylated Ser21/9 in GSK-3α/13 and body weight were lower （P 〈0.05）. However, the thickness of the retinal nerve epithelial layer was not significantly less in diabetic rats compared with control group. Lithium chloride intravitreal injection increased the levels of phosphorylated Ser21/9 in GSK-3α/13 and decreased TUNEL-positive cells in the whole-mounted retinas. Conclusion GSK-3 kinase is closely related to retinal neuron apoptosis, and the application of the GSK-3 inhibitor lithium chloride can reduce retinal neuron apoptosis in early diabetic retinopathy.展开更多
大量研究报告显示,糖原合成酶激酶-3(glycogen synthase kinase3,GSK3)在阿尔茨海默病(Alzheimer s dis-ease,AD)发病机制中起着重要的作用。AD患者存在GSK3活性的增强和水平的提高。细胞培养、无脊椎动物和哺乳类动物模型研究发现,GSK...大量研究报告显示,糖原合成酶激酶-3(glycogen synthase kinase3,GSK3)在阿尔茨海默病(Alzheimer s dis-ease,AD)发病机制中起着重要的作用。AD患者存在GSK3活性的增强和水平的提高。细胞培养、无脊椎动物和哺乳类动物模型研究发现,GSK3活性增强导致tau的过度磷酸化、Aβ产生的增加、学习和记忆能力的缺损,同时伴有神经退行性变。GSK3抑制剂能防止AD转基因动物tau的过度磷酸化,使得GSK3抑制剂有望用于预防和治疗AD。展开更多
基金the National Natural Science Foundation of China,No.30870876the Natural Science Foundation of Guangdong Province,No.815101700100005+2 种基金the Science and Technology Program of Guangdong Province,No.2005B60302004,2008B030301371,2009B030801368the Traditional Chinese Medicineand Combination of Traditional Chinese and Western Medicine Program of Guangzhou,No.2008A52the Medical and Health Scientific Research Program of Guangzhou,No.2009-YB-167
文摘In the present study,Fmr1 knockout mice （KO mice） were used as the model for fragile X syndrome.The results of step-through and step-down tests demonstrated that Fmr1 KO mice had shorter latencies and more error counts,indicating a learning and memory disorder.After treatment with 30,60,90,120,or 200 mg/kg lithium chloride,the learning and memory abilities of the Fmr1 KO mice were significantly ameliorated,in particular,the 200 mg/kg lithium chloride treatment had the most significant effect.Western blot analysis showed that lithium chloride significantly enhanced the expression of phosphorylated glycogen synthase kinase 3 beta,an inactive form of glycogen synthase kinase 3 beta,in the cerebral cortex and hippocampus of the Fmr1 KO mice.These results indicated that lithium chloride improved learning and memory in the Fmr1 KO mice,possibly by inhibiting glycogen synthase kinase 3 beta activity.
基金the National Natural Science Foundation of China, No. 30860085a grant from the Candidates of Young and Middle-Aged Academic Leaders of Yunnan Province, No. 2006PY01-07the Natural Science Foundation of Yunnan Province, No. 2007C177M
文摘1-methyl-4-phenylpyridinium ion （MPP^＋） induces endoplasmic reticulum stress and activates caspase-12 in PC12 cells, leading to neuronal apoptosis. However, the underlying molecular mechanism remains unknown. The present study investigated the regulatory effects of nerve growth factor （Akt activator） and lithium chloride （glycogen synthase kinase-3β inhibitor） on the endoplasmic reticulum stress signaling pathway. The results revealed that MPP＋ induced expression of Bip and C/EBP homologous protein. The upregulation of Bip and C/EBP homologous protein, as well as the decreased pro-caspase-12 level induced by MPP^＋ were inhibited by pretreatment of the nerve growth factor or lithium chloride. These results suggest that the phosphatidylinositol 3 kinase-Aktglycogen synthase kinase-3β pathway is involved in MPP-induced endoplasmic reticulum stress.
基金supported by grants from the National Natural Science Foundation of China(No.92049107 and No.31929002)the Innovative Research Groups of the National Natural Science Foundation of China(No.81721005)the Academic Frontier Youth Team Project to Xiaochuan Wang from Huazhong University of Science and Technology.
文摘Alzheimer’s disease (AD) is the most prevalent cause of dementia worldwide. Because of the progressive neurodegeneration, individual cognitive and behavioral functions are impaired, affecting the quality of life of millions of people. Although the exact pathogenesis of AD has not been fully elucidated, amyloid plaques, neurofibrillary tangles (NFTs), and sustaining neuroinflammation dominate its characteristics. As one of the major tau kinases leading to hyperphosphorylation and aggregation of tau, glycogen synthase kinase-3β (GSK-3β) has been drawing great attention in various AD studies. Another research focus of AD in recent years is the inflammasome, a multiprotein complex acting as a regulator in immunological reactions to exogenous and endogenous danger signals, of which the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome has been studied mostly in AD and proven to play a significant role in AD development by its activation and downstream effects such as caspase-1 maturation and interleukin (IL)-1β release. Studies have shown that the NLRP3 inflammasome is activated in a GSK-3β-dependent way and that inhibition of the NLRP3 inflammasome downregulates GSK-3β, suggesting that these two important proteins are closely related. This article reviews the respective roles of GSK-3β and the NLRP3 inflammasome in AD as well as their relationship and interaction.
文摘Tau oligomers are the etiologic molecules of Alzheimer disease(AD), and correlate strongly with neuronal loss and exhibit neurotoxicity. Recent evidence indicates that small tau oligomers are the most relevant toxic aggregate species. The aim of the present study was to investigate the mechanisms of cornel iridoid glycoside(CIG) on tau oligomers and cognitive functions. We injected wortmannin and GF-109203 X(WM/GFX, 200 μmol·L-1 each) into the lateral ventricles to induce tau oligomer and memory impairment in rats. When oral y administered with CIG at 60 and 120 mg·kg-1 per day for 14 d, CIG decreased the escape latency in Morris water maze test. We also found that CIG restored the expression of presynaptic p-synapsin, synaptophysin, and postsynaptic density-95(PSD-95) decreased by WM/GFX in rat cortex. CIG reduced the accumulation of tau oligomers in the brain of WM/GFX rats and in cells transfected with wild type glycogen synthase kinase-3β(wt GSK-3β). In addition, CIG up-regulated the levels of ATG7, ATG12, Beclin-1, and LC3 II in vivo and in vitro, suggesting the restoration of autophagy function. These results suggest that CIG could ameliorate memory deficits and regulate memory-associated synaptic proteins through the clearance of tau oligomers accumulation. Moreover, CIG clears tau oligomers by restoring autophagy function.
基金supported by the National Natural Science Foundation of China,Nos.81901994(to BZ)and 81571147(to XXX)the Natural Science Foundation of Hubei Province,China,No.2019CFC847(to WWG)the Fundamental Research Funds for the Central Universities,China,No.2042018kf0149(to ML)
文摘Interleukin-4(IL-4) has a protective effect against cerebral ischemia/reperfusion injury. Animal experiments have shown that IL-4 improves the short-and long-term prognosis of neurological function. The Akt(also called protein kinase B, PKB)/glycogen synthase kinase-3β(Akt/GSK-3β) signaling pathway is involved in oxidative stress, the inflammatory response, apoptosis, and autophagy. However, it is not yet clear whether the Akt/GSK-3β pathway participates in the neuroprotective effect of IL-4 against cerebral ischemia/reperfusion injury. In the present study, we established a cerebral ischemia/reperfusion mouse model by middle cerebral artery occlusion for 60 minutes followed by a 24-hour reperfusion. An IL-4/anti-IL-4 complex(10 μg) was intraperitoneally administered 30 minutes before surgery. We found that administration of IL-4 significantly alleviated the neurological deficits, oxidative stress, cell apoptosis, and autophagy and reduced infarct volume of the mice with cerebral ischemia/reperfusion injury 24 hours after reperfusion. Simultaneously, IL-4 activated Akt/GSK-3β signaling pathway. However, an Akt inhibitor LY294002, which was injected at 15 nmol/kg via the tail vein, attenuated the protective effects of IL-4. These findings indicate that IL-4 has a protective effect on cerebral ischemia/reperfusion injury by mitigating oxidative stress, reducing apoptosis, and inhibiting excessive autophagy, and that this mechanism may be related to activation of the Akt/GSK-3β pathway. This animal study was approved by the Animal Ethics Committee of Renmin Hospital of Wuhan University, China(approval No. WDRY2017-K037) on March 9, 2017.
基金sponsored by the National Natural Science Foundation of China,No.81170768
文摘The present study established global brain ischemia using the four-vessel occlusion method. Following three rounds of reperfusion for 30 seconds, and occlusion for 10 seconds, followed by reperfusion for 48 hours, infarct area, the number of TUNEL-positive cells and Bcl-2 expression were significantly reduced. However, glycogen synthase kinase-3β activity, cortical Bax and caspase-3 expression significantly increased, similar to results following ischemic postconditioning. Our results indicated that ischemic postconditioning may enhance glycogen synthase kinase-3β activity, a downstream molecule of the phosphatase and tensin homolog deleted on chromosome 10/phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which reduces caspase-3 expression to protect the brain against ischemic injury.
基金supported by the National Natural Science Foundation of China,No.81471844the Natural Science Foundation of Hubei Province of China,No.2016CFB167the Basic Scientific Research Foundation of Central Universities,No.2042017kf0147
文摘Myocardial ischemia/reperfusion injury can lead to severe brain injury.Glycogen synthase kinase 3 beta is known to be involved in myocardial ischemia/reperfusion injury and diabetes mellitus.However,the precise role of glycogen synthase kinase 3 beta in myocardial ischemia/reperfusion injury-induced brain injury is unclear.In this study,we observed the effects of glycogen synthase kinase 3 beta on brain injury induced by myocardial ischemia/reperfusion injury in diabetic rats.Rat models of diabetes mellitus were generated via intraperitoneal injection of streptozotocin.Models of myocardial ischemia/reperfusion injury were generated by occluding the anterior descending branch of the left coronary artery.Post-conditioning comprised three cycles of ischemia/reperfusion.Immunohistochemical staining and western blot assays demonstrated that after 48 hours of reperfusion,the structure of the brain was seriously damaged in the experimental rats compared with normal controls.Expression of Bax,interleukin-6,interleukin-8,terminal deoxynucleotidyl transferase d UTP nick end labeling,and cleaved caspase-3 in the brain was significantly increased,while expression of Bcl-2,interleukin-10,and phospho-glycogen synthase kinase 3 beta was decreased.Diabetes mellitus can aggravate inflammatory reactions and apoptosis.Ischemic post-conditioning with glycogen synthase kinase 3 beta inhibitor lithium chloride can effectively reverse these changes.Our results showed that myocardial ischemic post-conditioning attenuated myocardial ischemia/reperfusion injury-induced brain injury by activating glycogen synthase kinase 3 beta.According to these results,glycogen synthase kinase 3 beta appears to be an important factor in brain injury induced by myocardial ischemia/reperfusion injury.
文摘Multiple roles of glycogen synthase kinase-3（GSK-3）in neural tissues：GSK-3 is a serine/threonine kinase that has two isoforms encoded by two different genes,GSK-3αand GSK-3β,in mammals.GSK-3 has several sites of serine and tyrosine phosphorylation.
基金This work was supported by a grant from the National Natural Science Foundation of China （No. 81370185）.
文摘Background： Cognitive impairment is a severe complication caused by obstructive sleep apnea （OSA）. The mechanisms of causation are still unclear. The Wntβ-catenin signaling pathway is involved in cognition, and abnormalities in it are implicated in neurological disorders. Here, we explored the Wntβ-catenin signaling pathway abnormalities caused by chronic intermittent hypoxia （CIH）, the most characteristic pathophysiological component of OSA. Methods： We divided 32 4-week-old male C57/BL mice into four groups of eight each： a CIH ＋ normal saline （NS） group, CIH ＋ LiCI group, sham CIH ＋ NS group, and a sham CIH ＋ LiCI group. The spatial learning performance of each group was assessed by using the Morris water maze （MWM）. Protein expressions of glycogen synthase kinase-β （GSK-β） and β-catenin in the hippocampus were examined using the Western blotting test. EdU labeling and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining methods were used, respectively, to determine the proliferation and apoptosis of neurons in the hippocampal dentate gyrus region. Results： Mice exposed to CIH showed impaired spatial learning performance in the MWM, including increased mean escape latencies to reach the target platform, decreased mean times passing through the target platform and mean duration in the target quadrant. The GSK-313 activity increased, and expression of β-catenin decreased significantly in the hippocampus of the CIH-exposed mice. Besides, CIH significantly increased hippocampal neuronal apoptosis, with an elevated apoptosis index. Meanwhile, LiCI decreased the activity of GSK-β and increased the expression of β-catenin and partially reversed the spatial memory deficits in MWM and the apoptosis caused by CIH. Conclusions： Wntβ-catenin signaling pathway abnormalities possibly play an important role in the development of cognitive deficits among mice exposed to CIH and that LiCI might attenuate CIH-induced cognitive impairment via Wntβ-catenin signaling pathway.
基金supported by a grant provided by Southeast University(No.9224007044)
文摘Insulin resistance is the pathophysiological basis of many diseases.Overcoming early insulin resistance highly significant in prevention diabetes,non-alcoholic fatty liver,and atherosclerosis.The present study aimed at evaluating the therapeutic effects of baicalin on insulin resistance and skeletal muscle ectopic fat storage in high fat diet-induced mice,and exploring the potential molecular mechanisms.Insulin resistance in mice was induced with a high fat diet for 16 weeks.Animals were then treated with three different doses of baicalin(100,200,and 400 mg·kg^(-1)·d^(-1)for 14 weeks.Fasting blood glucose,fasting serum insulin,glucose tolerance test(GTT),insulin tolerance test(ITT),and skeletal muscle lipid deposition were measured.Additionally,the AMP-activated protein kinase/acetyl-CoA carboxylase and protein kinase B/Glycogen synthase kinase 3 beta pathways in skeletal muscle were further evaluated.Baicalin significantly reduced the levels of fasting blood glucose and fasting serum insulin and attenuated high fat diet induced glucose tolerance and insulin tolerance.Moreover,insulin resistance was significantly reversed.Pathological analysis revealed baicalin dose-dependently decreased the degree of the ectopic fat storage in skeletal muscle.The properties of baicalin were mediated,at least in part,by inhibition of the AMPK/ACC pathway,a key regulator of de novo lipogenesis and activation of the Akt/GSK-3β pathway,a key regulator of Glycogen synthesis.These data suggest that baicalin,at dose up to 400 mg·kg^(-1)·d^(-1),is safe and able to attenuate insulin resistance and skeletal muscle ectopic fat storage,through modulating the skeletal muscle AMPK/ACC pathway and Akt/GSK-3β pathway.
基金This study was supported by a grant from the National Nature Science Foundation of China （No. 81170863）.
文摘Background Diabetes-related pathogenic factors can cause retinal ganglion cell （RGC） apoptosis, but the specific mechanism is not very clear. The aim of this study is to investigate the correlation between glycogen synthase kinase-3 （GSK-3） activation and retinal neuron apoptosis. Methods In an in vitro experiment, the number of apoptotic RGC-5 cells differentiated by staurosporine was evaluated via flow cytometry and nuclei staining using Hoechst 33258. GSK-3 phosphorylation and caspase-3 activation in RGC-5 cells after serum deprivation were determined using Western blotting. Mitochondrial membrane potential was detected using the dye 5,5＇,6,6＇-tetrachloro-l,l＇,3,3＇-tetrethyl benzimidalyl carbocyanine iodide, and reactive oxygen species （ROS） levels were measured with dihydroethidium. In an in vivo experiment, the number of apoptotic retinal neurons was evaluated via terminal transferase dUTP nick-end labeling （TUNEL）, and GSK-3 phosphorylation was determined using Western blotting, in the retinal nerve epithelial tissue of rats in which diabetes was induced by intravenous tail-vein injection of streptozotocin for 4 weeks. Results The levels of phosphorylated Ser21/9 in GSK-3α/13 and p-T308/S473-AKT were lower and the cleaved caspase-3 levels were higher in the serum-deprived model （P 〈0.05）. Lithium chloride treatment was associated with a slower rate of apoptosis, increased mitochondrial membrane potential, and decreased ROS levels in differentiated RGC-5 cells （P 〈0.05）. The level of blood glucose and the number of TUNEL-positive cells in the whole-mounted retinas were higher （P 〈0.01）, and the levels of phosphorylated Ser21/9 in GSK-3α/13 and body weight were lower （P 〈0.05）. However, the thickness of the retinal nerve epithelial layer was not significantly less in diabetic rats compared with control group. Lithium chloride intravitreal injection increased the levels of phosphorylated Ser21/9 in GSK-3α/13 and decreased TUNEL-positive cells in the whole-mounted retinas. Conclusion GSK-3 kinase is closely related to retinal neuron apoptosis, and the application of the GSK-3 inhibitor lithium chloride can reduce retinal neuron apoptosis in early diabetic retinopathy.
文摘大量研究报告显示,糖原合成酶激酶-3(glycogen synthase kinase3,GSK3)在阿尔茨海默病(Alzheimer s dis-ease,AD)发病机制中起着重要的作用。AD患者存在GSK3活性的增强和水平的提高。细胞培养、无脊椎动物和哺乳类动物模型研究发现,GSK3活性增强导致tau的过度磷酸化、Aβ产生的增加、学习和记忆能力的缺损,同时伴有神经退行性变。GSK3抑制剂能防止AD转基因动物tau的过度磷酸化,使得GSK3抑制剂有望用于预防和治疗AD。
