The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully unders...The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.展开更多
Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,...Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,Sprague-Dawley(SD)rats were exposed to ZEN at a dosage of 5 mg/kg/day b.w.for a duration of 14 days.The results demonstrated that ZEN exposure led to notable pathological alterations and immunosuppression within the intestine.Furthermore,ZEN exposure caused a significant reduction in the levels of apolipoprotein E(ApoE)and liver X receptor(LXR)(P<0.05).Conversely,it upregulated the levels of myeloid-derived suppressor cells(MDSCs)markers(P<0.05)and decreased the presence of 27-hydroxycholesterol(27-HC)in the intestine(P<0.05).It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN.Additionally,a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal,breast,and lung cancers.These findings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine.Notably,ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.展开更多
目的探讨血清同型半胱氨酸(homocysteine,Hcy)、载脂蛋白E(apolipoprotein E,ApoE)基因多态性对血管性痴呆患者认知功能的影响。方法回顾性分析于医院接受治疗的100例血管性痴呆患者病例资料作为研究对象,使用简易智力状态检查量表(mini...目的探讨血清同型半胱氨酸(homocysteine,Hcy)、载脂蛋白E(apolipoprotein E,ApoE)基因多态性对血管性痴呆患者认知功能的影响。方法回顾性分析于医院接受治疗的100例血管性痴呆患者病例资料作为研究对象,使用简易智力状态检查量表(mini-mental state examination,MMSE)评估患者认知功能,将MMSE评分为21~26分患者纳入轻度组,将10~20分患者纳入中度组,将0~9分患者纳入重度组。参照《中国痴呆与认知障碍诊治指南》给予患者常规治疗,治疗前主要检查项目包括血浆Hcy、ApoE基因多态性,治疗3个月后记录患者临床疗效;分析ApoE基因多态性、Hcy与血管性痴呆患者认知功能障碍及临床疗效的关系。结果100例血管性痴呆患者MMSE评分为16.50(9.00,20.00)分,其中轻度24例,中度49例,重度27例;重度组ApoE基因表型为ε2/4、ε4/4患者占比高于轻度组、中度组,入院时血浆Hcy水平高于轻度组、中度组,差异有统计学意义(P<0.05);行多元Logistic回归分析结果显示,血浆Hcy、ApoE基因是导致血管性痴呆患者认知功能障碍加重的危险因素(P<0.05);100例血管性痴呆患者,治疗3个月后,显效47例,好转30例,无效23例,总有效率为77.00%;行二元Logistic回归分析显示,血浆Hcy、ApoE基因均是影响血管性痴呆患者治疗效果的危险因素(P<0.05)。结论ApoE基因多态性、Hcy与血管性痴呆患者认知功能障碍病情严重程度及临床关系密切,未来临床可通过检测患者ApoE基因多态性、Hcy水平,评估患者认知障碍严重程度及治疗无效风险,针对病情严重治疗无效风险较高者,采取针对性干预,以改善患者临床疗效。展开更多
Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evoluti...Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of Alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in Alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease.展开更多
Background: Apolipoprotein E2(ApoE2) is a pleiotropic protein that influences several aspects of cancer metabolism and development. Evading apoptosis is a vital factor for facilitating cancer cell growth. However, the...Background: Apolipoprotein E2(ApoE2) is a pleiotropic protein that influences several aspects of cancer metabolism and development. Evading apoptosis is a vital factor for facilitating cancer cell growth. However, the role and mechanism of ApoE2 in regulating cell apoptosis of pancreatic cancer remain unclear. Methods: In this study, we firstly detected the m RNA and protein expressions of ApoE2 in PANC-1 and Capan-2 cells by real-time polymerase chain reaction and Western blotting. We then performed TUNEL and flow cytometric analyses to explore the role of recombinant human ApoE2, p CMV6-ApoE2 and si ApoE2 in the apoptosis of PANC-1 and Capan-2 cells. Furthermore, we investigated the molecular mechanism through which ApoE2 affected apoptosis in PANC-1 cells using immunofluorescence, immunoprecipitation, Western blotting and co-immunoprecipitation analysis. Results: ApoE2 phosphorylated ERK1/2 and inhibited pancreatic cancer cell apoptosis. In addition, our data showed that ApoE2/ERK1/2 altered the expression and mitochondrial localization of BCL-2 via activating CREB. ApoE2/ERK1/2/CREB also increased the total BCL-2/BAX ratio, inhibited the opening of the mitochondrial permeability transition pore and the depolarization of mitochondrial transmembrane potential, blocked the leakage of cytochrome-c and the formation of the apoptosome, and consequently, suppressed mitochondrial apoptosis. Conclusions: ApoE2 regulates the mitochondrial localization and expression of BCL-2 through the activation of the ERK1/2/CREB signaling cascade to evade the mitochondrial apoptosis of pancreatic cancer cells. ApoE2 may be a distinct prognostic marker and a potential therapeutic target for pancreatic cancer.展开更多
At present,ischemic stroke seriously affects people's life and health,and its occurrence,development and therapeutic effect are affected by many factors.With the deep research on ischemic cerebral apoplexy disease...At present,ischemic stroke seriously affects people's life and health,and its occurrence,development and therapeutic effect are affected by many factors.With the deep research on ischemic cerebral apoplexy disease,people have a deeper understanding of its virulence genes.The apolipoprotein E genotype is the research focus recently,its genetic type is not only involved in the occurrence and development of ischemic cerebral apoplexy,but also causes different therapeatic effects.In this paper,we reviewed the relationship between apolipoprotein E gene polymorphism and lipid metabolism and atherosclerosis in ischemic stroke,as well as the differences in the therapeutic effects of thrombolysis,thrombectomy and lipid-lowering among different genotypes.展开更多
Apolipoprotein E is the major lipid transporter in the brain and an important player in neuron-astrocyte metabolic coupling.It ensures the survival of neurons under stressful conditions and hyperactivity by nourishing...Apolipoprotein E is the major lipid transporter in the brain and an important player in neuron-astrocyte metabolic coupling.It ensures the survival of neurons under stressful conditions and hyperactivity by nourishing and detoxifying them.Apolipoprotein E polymorphism,combined with environmental stresses and/or age-related alterations,influences the risk of developing late-onset Alzheimer’s disease.In this review,we discuss our current knowledge of how apolipoprotein E homeostasis,i.e.its synthesis,secretion,degradation,and lipidation,is affected in Alzheimer’s disease.展开更多
Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primar...Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.展开更多
文摘The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.
基金the Fundamental Research Funds for the Central Universities,China(Grant No.:3332022147)the CAMS Innovation Fund for Medical Sciences,China(Grant Nos.:2021-I2M-1-071 and 2021-I2M-1-031)the National Natural Science Foundation of China(Grant No.:81872999).
文摘Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,Sprague-Dawley(SD)rats were exposed to ZEN at a dosage of 5 mg/kg/day b.w.for a duration of 14 days.The results demonstrated that ZEN exposure led to notable pathological alterations and immunosuppression within the intestine.Furthermore,ZEN exposure caused a significant reduction in the levels of apolipoprotein E(ApoE)and liver X receptor(LXR)(P<0.05).Conversely,it upregulated the levels of myeloid-derived suppressor cells(MDSCs)markers(P<0.05)and decreased the presence of 27-hydroxycholesterol(27-HC)in the intestine(P<0.05).It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN.Additionally,a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal,breast,and lung cancers.These findings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine.Notably,ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.
文摘目的探讨血清同型半胱氨酸(homocysteine,Hcy)、载脂蛋白E(apolipoprotein E,ApoE)基因多态性对血管性痴呆患者认知功能的影响。方法回顾性分析于医院接受治疗的100例血管性痴呆患者病例资料作为研究对象,使用简易智力状态检查量表(mini-mental state examination,MMSE)评估患者认知功能,将MMSE评分为21~26分患者纳入轻度组,将10~20分患者纳入中度组,将0~9分患者纳入重度组。参照《中国痴呆与认知障碍诊治指南》给予患者常规治疗,治疗前主要检查项目包括血浆Hcy、ApoE基因多态性,治疗3个月后记录患者临床疗效;分析ApoE基因多态性、Hcy与血管性痴呆患者认知功能障碍及临床疗效的关系。结果100例血管性痴呆患者MMSE评分为16.50(9.00,20.00)分,其中轻度24例,中度49例,重度27例;重度组ApoE基因表型为ε2/4、ε4/4患者占比高于轻度组、中度组,入院时血浆Hcy水平高于轻度组、中度组,差异有统计学意义(P<0.05);行多元Logistic回归分析结果显示,血浆Hcy、ApoE基因是导致血管性痴呆患者认知功能障碍加重的危险因素(P<0.05);100例血管性痴呆患者,治疗3个月后,显效47例,好转30例,无效23例,总有效率为77.00%;行二元Logistic回归分析显示,血浆Hcy、ApoE基因均是影响血管性痴呆患者治疗效果的危险因素(P<0.05)。结论ApoE基因多态性、Hcy与血管性痴呆患者认知功能障碍病情严重程度及临床关系密切,未来临床可通过检测患者ApoE基因多态性、Hcy水平,评估患者认知障碍严重程度及治疗无效风险,针对病情严重治疗无效风险较高者,采取针对性干预,以改善患者临床疗效。
基金supported by the National Natural Science Foundation of China,No.81501106(to CF)Fund of Taishan Scholar Project(to CF)+1 种基金the Natural Science Foundation of Shandong Province,No.ZR2020QH106(to YH)the Medical and Health Science and Technology Development Plan of Shandong Province,No.202203010799(to QS)。
文摘Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of Alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in Alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease.
基金supported by grants from the National Natural Science Foundation of China (31370861)the Tianjin Basic Re-search Plan Project (13JCZDJC31300)。
文摘Background: Apolipoprotein E2(ApoE2) is a pleiotropic protein that influences several aspects of cancer metabolism and development. Evading apoptosis is a vital factor for facilitating cancer cell growth. However, the role and mechanism of ApoE2 in regulating cell apoptosis of pancreatic cancer remain unclear. Methods: In this study, we firstly detected the m RNA and protein expressions of ApoE2 in PANC-1 and Capan-2 cells by real-time polymerase chain reaction and Western blotting. We then performed TUNEL and flow cytometric analyses to explore the role of recombinant human ApoE2, p CMV6-ApoE2 and si ApoE2 in the apoptosis of PANC-1 and Capan-2 cells. Furthermore, we investigated the molecular mechanism through which ApoE2 affected apoptosis in PANC-1 cells using immunofluorescence, immunoprecipitation, Western blotting and co-immunoprecipitation analysis. Results: ApoE2 phosphorylated ERK1/2 and inhibited pancreatic cancer cell apoptosis. In addition, our data showed that ApoE2/ERK1/2 altered the expression and mitochondrial localization of BCL-2 via activating CREB. ApoE2/ERK1/2/CREB also increased the total BCL-2/BAX ratio, inhibited the opening of the mitochondrial permeability transition pore and the depolarization of mitochondrial transmembrane potential, blocked the leakage of cytochrome-c and the formation of the apoptosome, and consequently, suppressed mitochondrial apoptosis. Conclusions: ApoE2 regulates the mitochondrial localization and expression of BCL-2 through the activation of the ERK1/2/CREB signaling cascade to evade the mitochondrial apoptosis of pancreatic cancer cells. ApoE2 may be a distinct prognostic marker and a potential therapeutic target for pancreatic cancer.
基金Major Science and Technology Project of Hainan Province(ZDKJ202004)。
文摘At present,ischemic stroke seriously affects people's life and health,and its occurrence,development and therapeutic effect are affected by many factors.With the deep research on ischemic cerebral apoplexy disease,people have a deeper understanding of its virulence genes.The apolipoprotein E genotype is the research focus recently,its genetic type is not only involved in the occurrence and development of ischemic cerebral apoplexy,but also causes different therapeatic effects.In this paper,we reviewed the relationship between apolipoprotein E gene polymorphism and lipid metabolism and atherosclerosis in ischemic stroke,as well as the differences in the therapeutic effects of thrombolysis,thrombectomy and lipid-lowering among different genotypes.
基金supported by the financial support of the Louis-Jeantet Foundation(to ACG).
文摘Apolipoprotein E is the major lipid transporter in the brain and an important player in neuron-astrocyte metabolic coupling.It ensures the survival of neurons under stressful conditions and hyperactivity by nourishing and detoxifying them.Apolipoprotein E polymorphism,combined with environmental stresses and/or age-related alterations,influences the risk of developing late-onset Alzheimer’s disease.In this review,we discuss our current knowledge of how apolipoprotein E homeostasis,i.e.its synthesis,secretion,degradation,and lipidation,is affected in Alzheimer’s disease.
基金financially supported by the Science and Technology Innovation Program of Hunan Province,No.2022RC1220(to WP)China Postdoctoral Science Foundation,No.2022M711733(to ZZ)+2 种基金the National Natural Science Foundation of China,No.82160920(to ZZ)Hebei Postdoctoral Scientific Research Project,No.B2022003040(to ZZ)Hunan Flagship Department of Integrated Traditional Chinese and Western Medicine(to WP)。
文摘Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.
