Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease(AD),which is closely related to tau pathology and hippocampal impairment.Due to the heterogeneity of brain neurons,the spec...Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease(AD),which is closely related to tau pathology and hippocampal impairment.Due to the heterogeneity of brain neurons,the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear.Therefore,further investigation is necessary.Methods:We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis,social behavioural tests,hippocampal electrophysiology,immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR.Additionally,we utilized optogenetics and administered ursolic acid(UA)via oral gavage to examine the effects of these agents on social memory in mice.Results:The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1(vCA1)under both physiological conditions and AD-like tau pathology.As tau progressively accumulated,vCA1,especially its excitatory and parvalbumin(PV)neurons,were fully filled with mislocated and phosphorylated tau(p-Tau).This finding was not observed for dorsal hippocampal CA1(dCA1).The overexpression of human tau(hTau)in excitatory and PV neurons mimicked AD-like tau accumulation,significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1.Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory.Notably,1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB(TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion:This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation.Notably,our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.展开更多
Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, bu...Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, but rarely Alzheimer’s disease. Adeno-associated virus carrying the CaMK promoter driving the optogenetic channelrhodopsin-2 (CHR2) gene (or without the CHR2 gene, as control) was injected into the bilateral dentate gyri, followed by repeated intrahippocampal injections of soluble low-molecular-weight amyloid-β1–42 peptide (Aβ1–42). Subsequently, the region was stimulated with a 473 nm laser (1–3 ms, 10 Hz, 5 minutes). The novel object recognition test was conducted to test memory function in mice. Immunohistochemical staining was performed to analyze the numbers of NeuN and synapsin Ia/b-positive cells in the hippocampus. Western blot assay was carried out to analyze the expression levels of glial fibrillary acidic protein, NeuN, synapsin Ia/b, metabotropic glutamate receptor-1a (mGluR-1a), mGluR-5, N-methyl-D-aspartate receptor subunit NR1, glutamate receptor 2, interleukin-1β, interleukin-6 and interleukin-10. Optogenetic stimulation improved working and short-term memory in mice with Alzheimer’s disease. This neuroprotective effect was associated with increased expression of NR1, glutamate receptor 2 and mGluR-5 in the hippocampus, and decreased expression of glial fibrillary acidic protein and interleukin-6. Our results show that optogenetics can be used to regulate the neuronal-glial network to ameliorate memory functions in mice with Alzheimer’s disease. The study was approved by the Animal Resources Committee of Jinan University, China (approval No. LL-KT-2011134) on February 28, 2011.展开更多
Trichloroethylene （TCE） is a major pollutant that affects both occupational and general environments. The liver is an important target organ of TCEE. Substantial efforts and remarkable progress into understanding TC...Trichloroethylene （TCE） is a major pollutant that affects both occupational and general environments. The liver is an important target organ of TCEE. Substantial efforts and remarkable progress into understanding TCE cytotoxicity have been made in cultured liver cells. However, the molecular mechanisms by which TCE induces hepatotoxicity are not well understood. SET （also known as protein phosphatase 2A inhibitor, 12PP2A, or template-activating factor-I, TAF-D is a nuclear protein that regulates histone modification, gene transcription, DNA replication, nucleosome assembly,展开更多
The aim of this study is to investigate epigenetic mechanism of ABCG2 induced drug-resistance. It is not only expatiate for drug-resistance regulation mechanism in all-round, but also to provide scientific experimenta...The aim of this study is to investigate epigenetic mechanism of ABCG2 induced drug-resistance. It is not only expatiate for drug-resistance regulation mechanism in all-round, but also to provide scientific experimental basis for selecting target to reverse its drug-resistance. Apply methylation-specific PCR （MSP） to have tested methylation of ABCG2 promoter region -359 to -353 specific positions in breast cancer tissues and paired adjacent tissue of 22 cases and test their methylation positions with MSP products for sequencing; and adopt fluorescent quantitation RT-PCR to test expression level DNMT1, DNMT3A, DNMT3B and ABCG2; to make analysis on relationship between them with statistical spearman correlation. Specific positions of ABCG2 gene promoter region of 18 cases among the 22 cases with breast cancer （18/22, 82%） existed high methylation （P〈0.05）, MSP products sequencing proved methylation of the specific position, and mRNA expression level was relative higher in remarkable positive correlation （P〈0.05） ABCG2, DNMT1, DNMT3A, DNMT3B mRNA expression levels in breast cancer tissues were obviously higher than adjacent tissues （P〈0.01）, and DNMT3B expression level was obviously higher than DNMT1 and DNMT3A （P〈0.01） in negative correlation with ABCG2 gene expression （P=0.001）. -359 to -353 positions of promoter regions of ABCG2gene existed high methylation capable to push expression of this gene in beast cancer tissue. DNMT3B is involved in expression regulation in ABCG2 gene, and provides new scientific basis for drug-resistance target as reverse ABCG2 induction展开更多
Alzheimer＇s disease （AD） is a fatal neurodegenerative disorder that takes about a decade to develop, making early diagnosis possible. Clinically, the diagnosis of AD is complicated, costly, and inaccurate, so it is...Alzheimer＇s disease （AD） is a fatal neurodegenerative disorder that takes about a decade to develop, making early diagnosis possible. Clinically, the diagnosis of AD is complicated, costly, and inaccurate, so it is urgent to find specific biomarkers. Due to its multifactorial nature, a panel of biomarkers for the multiple pathologies of AD, such as cerebral amyloidogenesis, neuronal dysfunction, synapse loss, oxidative stress, and inflammation, are most promising for accurate diagnosis. Highly sensitive and high-throughput proteomic techniques can be applied to develop a panel of novel biomarkers for AD. In this review, we discuss the metabolism and diagnostic performance of the well-established core candidate cerebrospinal fluid （CSF） biomarkers （β-amyloid, total tau, and hyperphosphorylated tau）. Meanwhile, novel promising CSF biomarkers, especially those identified by proteomics, updated in the last five years are also extensively discussed. Furthermore, we provide perspectives on how biomarker discovery for AD is evolving.展开更多
Gestational exposure to PM_(2.5) is associated with adverse postnatal outcomes.PM_(2.5) can enter alveoli by using intratracheal instillation,even penetrate through lung cells into the blood circulation.Subsequently,t...Gestational exposure to PM_(2.5) is associated with adverse postnatal outcomes.PM_(2.5) can enter alveoli by using intratracheal instillation,even penetrate through lung cells into the blood circulation.Subsequently,they are transferred across the placenta and fetal blood brain barrier,causing the adverse birth outcomes of offspring.This study demonstrated that the gestational exposure resulted in cognitive and emotional disorders in female offspring although the offspring were not exposed to PM_(2.5).Placental metabolic pathways modulated fetal brain development and played a pivotal role for maternal-placentalfetal interactions in the fetal programming of adult behavioral and mental disorders.Samples of fetus,offspring hippocampus and placenta from the mice exposed to PM_(2.5) were investigated using a comprehensive approach including mass spectrometry-based lipidomics and three-dimensional imaging.The exposure induced the neuro-degeneration in hippocampus,impairment of placental cytoarchitecture,and reprogramming of lipidome,which might affect the modulation of maternal-fetal cross-talk and result in the behavior disorders of offspring.The variation of spatial distribution of lipids was profoundly affected in dorsal pallium and hippocampal formation regions of fetal brain,offspring hippocampus,as well as labyrinth and junctional zones of placenta.The abundance alteration of lipid markers associated with neurodegenerative diseases was validated in transgenic mouse model with Alzheimer’s disease and human cerebrospinal fluid from patients with Parkinson’s disease.The finding could help with the selection of more suitable heterogeneous-related substructures targeting PM_(2.5) exposure and the exploration of PM_(2.5)-induced toxicological effects on neurodegenerative diseases.展开更多
Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor ...Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy.Proteolysis Targeting Chimeras(PROTAC)technology has emerged as a new model for drug research and development for its advantageous mechanism.Herein,we reported the application of PROTAC technology in targeted degradation of IDO 1,leading to the discovery of the first IDO1 PROTAC degrader 2 c,which induced significant and persistent degradation of IDO1 with maximum degradation(Dmax)of 93%in HeLa cells.Western-blot based mechanistic studies indicated that IDO 1 was degraded by 2 c through the ubiquitin proteasome system(UPS).Label-free real-time cell analysis(RTCA)indicated that 2 c moderately improved tumorkilling activity of chimeric antigen receptor-modified T(CAR-T)cells.Collectively,these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.展开更多
In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulati...In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1(STAT1)to inhibit the transcription of synaptic N-methyl-D-aspartate receptors(NMDARs).Here,overexpressing human P301L mutant tau(P301L-hTau)increased the phosphorylated level of Signal Transduction and Activator of Transcription-3(STAT3)at Tyr705 by JAK2,which would promote STAT3 translocate into the nucleus and activate STAT3.However,STAT3 was found mainly located in the cytoplasm.Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm,and thus inhibited the nuclear translocation and inactivation of STAT3.Knockdown of STAT3 in STAT3flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression,synaptic and memory impairments.Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression.Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters.These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression,revealed a novel mechanism for tau-associated synapse and cognition deficits,and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.展开更多
Dear Editor,Recently,lower hemoglobin/anemia in the elderly is found to be associated with cognitive impairment and Alzheimer’s disease(AD),1 implying that erythropoietin(EPO)may be of benefit for AD.As a clinically ...Dear Editor,Recently,lower hemoglobin/anemia in the elderly is found to be associated with cognitive impairment and Alzheimer’s disease(AD),1 implying that erythropoietin(EPO)may be of benefit for AD.As a clinically safe-to-use drug,besides its hematopoietic function,recombinant human EPO(rhEPO)is reported to present multifaceted neuroprotective effects.2 Unfortunately,few clinical studies investigated the effect of rhEPO in AD patients.展开更多
In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulati...In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1(STAT1)to inhibit the transcription of synaptic N-methyl-D-aspartate receptors(NMDARs).Here,overexpressing human P301L mutant tau(P301L-hTau)increased the phosphorylated level of Signal Transduction and Activator of Transcription-3(STAT3)at Tyr705 by JAK2,which would promote STAT3 translocate into the nucleus and activate STAT3.However,STAT3 was found mainly located in the cytoplasm.Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm,and thus inhibited the nuclear translocation and inactivation of STAT3.Knockdown of STAT3 in STAT3^(flox/flox) mice mimicked P301L-hTau-induced suppression of NMDARs expression,synaptic and memory impairments.Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression.Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters.These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression,revealed a novel mechanism for tau-associated synapse and cognition deficits,and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.展开更多
Background:Building brain reserves before dementia onset could represent a promising strategy to prevent Alzheimer’s disease(AD),while how to initiate early cognitive stimulation is unclear.Given that the immature br...Background:Building brain reserves before dementia onset could represent a promising strategy to prevent Alzheimer’s disease(AD),while how to initiate early cognitive stimulation is unclear.Given that the immature brain is more sensitive to environmental stimuli and that brain dynamics decrease with ageing,we reasoned that it would be effective to initiate cognitive stimulation against AD as early as the fetal period.Methods:After conception,maternal AD transgenic mice(3×Tg AD)were exposed to gestational environment enrichment(GEE)until the day of delivery.The cognitive capacity of the offspring was assessed by the Morris water maze and contextual fear-conditioning tests when the offspring were raised in a standard environment to 7 months of age.Western blotting,immunohistochemistry,real-time PCR,immunoprecipitation,chromatin immunoprecipitation(ChIP)assay,electrophysiology,Golgi staining,activity assays and sandwich ELISA were employed to gain insight into the mechanisms underlying the beneficial effects of GEE on embryos and 7–10-month-old adult offspring.Results:We found that GEE markedly preserved synaptic plasticity and memory capacity with amelioration of hallmark pathologies in 7–10-m-old AD offspring.The beneficial effects of GEE were accompanied by global histone hyperacetylation,including those at bdnf promoter-binding regions,with robust BDNF mRNA and protein expression in both embryo and progeny hippocampus.GEE increased insulin-like growth factor 1(IGF1)and activated its receptor(IGF1R),which phosphorylates Ca^(2+)/calmodulin-dependent kinase IV(CaMKIV)at tyrosine sites and triggers its nuclear translocation,subsequently upregulating histone acetyltransferase(HAT)and BDNF transcription.The upregulation of IGF1 mimicked the effects of GEE,while IGF1R or HAT inhibition during pregnancy abolished the GEE-induced CaMKIV-dependent histone hyperacetylation and BDNF upregulation.Conclusions:These findings suggest that activation of IGF1R/CaMKIV/HAT/BDNF signaling by gestational environment enrichment may serve as a promising strategy to delay AD progression.展开更多
基金supported in part by the National Natural Science Foundation of China(91949205,82071219,82001134,31730035,81721005,and 82201584)the Hubei Provincial Key S&T Program(2018ACA142)the Guangdong Provincial Key S&T Program(2018B030336001).
文摘Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease(AD),which is closely related to tau pathology and hippocampal impairment.Due to the heterogeneity of brain neurons,the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear.Therefore,further investigation is necessary.Methods:We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis,social behavioural tests,hippocampal electrophysiology,immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR.Additionally,we utilized optogenetics and administered ursolic acid(UA)via oral gavage to examine the effects of these agents on social memory in mice.Results:The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1(vCA1)under both physiological conditions and AD-like tau pathology.As tau progressively accumulated,vCA1,especially its excitatory and parvalbumin(PV)neurons,were fully filled with mislocated and phosphorylated tau(p-Tau).This finding was not observed for dorsal hippocampal CA1(dCA1).The overexpression of human tau(hTau)in excitatory and PV neurons mimicked AD-like tau accumulation,significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1.Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory.Notably,1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB(TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion:This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation.Notably,our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.
基金supported by the National Natural Science Foundation of China,No.81171191(to LYZ)the Shenzhen Special Fund Project on Strategic Emerging Industry Development of China,No.JCYJ20160422170522075(to LYZ)the Shenzhen Healthcare Research Project of China,No.201601015(to LYZ)
文摘Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, but rarely Alzheimer’s disease. Adeno-associated virus carrying the CaMK promoter driving the optogenetic channelrhodopsin-2 (CHR2) gene (or without the CHR2 gene, as control) was injected into the bilateral dentate gyri, followed by repeated intrahippocampal injections of soluble low-molecular-weight amyloid-β1–42 peptide (Aβ1–42). Subsequently, the region was stimulated with a 473 nm laser (1–3 ms, 10 Hz, 5 minutes). The novel object recognition test was conducted to test memory function in mice. Immunohistochemical staining was performed to analyze the numbers of NeuN and synapsin Ia/b-positive cells in the hippocampus. Western blot assay was carried out to analyze the expression levels of glial fibrillary acidic protein, NeuN, synapsin Ia/b, metabotropic glutamate receptor-1a (mGluR-1a), mGluR-5, N-methyl-D-aspartate receptor subunit NR1, glutamate receptor 2, interleukin-1β, interleukin-6 and interleukin-10. Optogenetic stimulation improved working and short-term memory in mice with Alzheimer’s disease. This neuroprotective effect was associated with increased expression of NR1, glutamate receptor 2 and mGluR-5 in the hippocampus, and decreased expression of glial fibrillary acidic protein and interleukin-6. Our results show that optogenetics can be used to regulate the neuronal-glial network to ameliorate memory functions in mice with Alzheimer’s disease. The study was approved by the Animal Resources Committee of Jinan University, China (approval No. LL-KT-2011134) on February 28, 2011.
基金supported by NSFC (the National Natural Science Foundation of China) [81273126, 30972454]the Key Project of Guangdong Natural Science Foundation [S2012020010903]+2 种基金the Project of Shenzhen Basic Research Plan [JCYJ20120616 154222545]the Upgrade Scheme of Shenzhen Municipal Key Laboratory [CXB201005260068A]Medical Scientific Research Foundation of Guangdong Province (A2012577)
文摘Trichloroethylene （TCE） is a major pollutant that affects both occupational and general environments. The liver is an important target organ of TCEE. Substantial efforts and remarkable progress into understanding TCE cytotoxicity have been made in cultured liver cells. However, the molecular mechanisms by which TCE induces hepatotoxicity are not well understood. SET （also known as protein phosphatase 2A inhibitor, 12PP2A, or template-activating factor-I, TAF-D is a nuclear protein that regulates histone modification, gene transcription, DNA replication, nucleosome assembly,
基金Supported by the National Natural Science Foundation of China (30500599 and 30571592)the Natural Science Foundation of Guangdong (9151503102000019)the Medical Scientific Research Foundation of Guangdong (A2009606)
文摘The aim of this study is to investigate epigenetic mechanism of ABCG2 induced drug-resistance. It is not only expatiate for drug-resistance regulation mechanism in all-round, but also to provide scientific experimental basis for selecting target to reverse its drug-resistance. Apply methylation-specific PCR （MSP） to have tested methylation of ABCG2 promoter region -359 to -353 specific positions in breast cancer tissues and paired adjacent tissue of 22 cases and test their methylation positions with MSP products for sequencing; and adopt fluorescent quantitation RT-PCR to test expression level DNMT1, DNMT3A, DNMT3B and ABCG2; to make analysis on relationship between them with statistical spearman correlation. Specific positions of ABCG2 gene promoter region of 18 cases among the 22 cases with breast cancer （18/22, 82%） existed high methylation （P〈0.05）, MSP products sequencing proved methylation of the specific position, and mRNA expression level was relative higher in remarkable positive correlation （P〈0.05） ABCG2, DNMT1, DNMT3A, DNMT3B mRNA expression levels in breast cancer tissues were obviously higher than adjacent tissues （P〈0.01）, and DNMT3B expression level was obviously higher than DNMT1 and DNMT3A （P〈0.01） in negative correlation with ABCG2 gene expression （P=0.001）. -359 to -353 positions of promoter regions of ABCG2gene existed high methylation capable to push expression of this gene in beast cancer tissue. DNMT3B is involved in expression regulation in ABCG2 gene, and provides new scientific basis for drug-resistance target as reverse ABCG2 induction
基金supported by the National Natural Science Foundation of China(81102154)the Medical Scientifi c Research Foundation of Guangdong Province,China(B2012322 and A2013598)+1 种基金Shenzhen Scheme of Science and Technology(Medicine and Health)(201202086 and 201302148)a Shenzhen Special Fund Project on Strategic Emerging Industry Development of China(JCYJ20130329103949650)
文摘Alzheimer＇s disease （AD） is a fatal neurodegenerative disorder that takes about a decade to develop, making early diagnosis possible. Clinically, the diagnosis of AD is complicated, costly, and inaccurate, so it is urgent to find specific biomarkers. Due to its multifactorial nature, a panel of biomarkers for the multiple pathologies of AD, such as cerebral amyloidogenesis, neuronal dysfunction, synapse loss, oxidative stress, and inflammation, are most promising for accurate diagnosis. Highly sensitive and high-throughput proteomic techniques can be applied to develop a panel of novel biomarkers for AD. In this review, we discuss the metabolism and diagnostic performance of the well-established core candidate cerebrospinal fluid （CSF） biomarkers （β-amyloid, total tau, and hyperphosphorylated tau）. Meanwhile, novel promising CSF biomarkers, especially those identified by proteomics, updated in the last five years are also extensively discussed. Furthermore, we provide perspectives on how biomarker discovery for AD is evolving.
基金supported by the National Natural Science Foundation of China(91843301)the National Key Research Program of China(2017YFC1600505 and 2017YFE0191000)+1 种基金Sanming Project of Medicine in Shenzhen of China(SZSM201811070)General Research Fund from Hong Kong Research Grants Council(12303320)。
文摘Gestational exposure to PM_(2.5) is associated with adverse postnatal outcomes.PM_(2.5) can enter alveoli by using intratracheal instillation,even penetrate through lung cells into the blood circulation.Subsequently,they are transferred across the placenta and fetal blood brain barrier,causing the adverse birth outcomes of offspring.This study demonstrated that the gestational exposure resulted in cognitive and emotional disorders in female offspring although the offspring were not exposed to PM_(2.5).Placental metabolic pathways modulated fetal brain development and played a pivotal role for maternal-placentalfetal interactions in the fetal programming of adult behavioral and mental disorders.Samples of fetus,offspring hippocampus and placenta from the mice exposed to PM_(2.5) were investigated using a comprehensive approach including mass spectrometry-based lipidomics and three-dimensional imaging.The exposure induced the neuro-degeneration in hippocampus,impairment of placental cytoarchitecture,and reprogramming of lipidome,which might affect the modulation of maternal-fetal cross-talk and result in the behavior disorders of offspring.The variation of spatial distribution of lipids was profoundly affected in dorsal pallium and hippocampal formation regions of fetal brain,offspring hippocampus,as well as labyrinth and junctional zones of placenta.The abundance alteration of lipid markers associated with neurodegenerative diseases was validated in transgenic mouse model with Alzheimer’s disease and human cerebrospinal fluid from patients with Parkinson’s disease.The finding could help with the selection of more suitable heterogeneous-related substructures targeting PM_(2.5) exposure and the exploration of PM_(2.5)-induced toxicological effects on neurodegenerative diseases.
文摘Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy.Proteolysis Targeting Chimeras(PROTAC)technology has emerged as a new model for drug research and development for its advantageous mechanism.Herein,we reported the application of PROTAC technology in targeted degradation of IDO 1,leading to the discovery of the first IDO1 PROTAC degrader 2 c,which induced significant and persistent degradation of IDO1 with maximum degradation(Dmax)of 93%in HeLa cells.Western-blot based mechanistic studies indicated that IDO 1 was degraded by 2 c through the ubiquitin proteasome system(UPS).Label-free real-time cell analysis(RTCA)indicated that 2 c moderately improved tumorkilling activity of chimeric antigen receptor-modified T(CAR-T)cells.Collectively,these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.
基金supported in parts by Natural Science Foundation of China(81870846)the Ministry of Science and Technology of China(2016YFC13058001)Sanming Project of Medicine in Shenzhen(SZSM201611090).
文摘In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1(STAT1)to inhibit the transcription of synaptic N-methyl-D-aspartate receptors(NMDARs).Here,overexpressing human P301L mutant tau(P301L-hTau)increased the phosphorylated level of Signal Transduction and Activator of Transcription-3(STAT3)at Tyr705 by JAK2,which would promote STAT3 translocate into the nucleus and activate STAT3.However,STAT3 was found mainly located in the cytoplasm.Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm,and thus inhibited the nuclear translocation and inactivation of STAT3.Knockdown of STAT3 in STAT3flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression,synaptic and memory impairments.Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression.Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters.These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression,revealed a novel mechanism for tau-associated synapse and cognition deficits,and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.
基金supported in parts by the Natural Science Foundation of China(82071221 and 81870846).
文摘Dear Editor,Recently,lower hemoglobin/anemia in the elderly is found to be associated with cognitive impairment and Alzheimer’s disease(AD),1 implying that erythropoietin(EPO)may be of benefit for AD.As a clinically safe-to-use drug,besides its hematopoietic function,recombinant human EPO(rhEPO)is reported to present multifaceted neuroprotective effects.2 Unfortunately,few clinical studies investigated the effect of rhEPO in AD patients.
基金This work was supported in parts by Natural Science Foundation of China(81870846)the Ministry of Science and Technology of China(2016YFC13058001)Sanming Project of Medicine in Shenzhen(SZSM201611090).
文摘In tauopathies,memory impairment positively strongly correlates with the amount of abnormal tau aggregates;however,how tau accumulation induces synapse impairment is unclear.Recently,we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1(STAT1)to inhibit the transcription of synaptic N-methyl-D-aspartate receptors(NMDARs).Here,overexpressing human P301L mutant tau(P301L-hTau)increased the phosphorylated level of Signal Transduction and Activator of Transcription-3(STAT3)at Tyr705 by JAK2,which would promote STAT3 translocate into the nucleus and activate STAT3.However,STAT3 was found mainly located in the cytoplasm.Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm,and thus inhibited the nuclear translocation and inactivation of STAT3.Knockdown of STAT3 in STAT3^(flox/flox) mice mimicked P301L-hTau-induced suppression of NMDARs expression,synaptic and memory impairments.Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression.Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters.These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression,revealed a novel mechanism for tau-associated synapse and cognition deficits,and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.
基金This work was supported in part by grants from the NSFC(91632305,91632111,31730035 and 81721005)by the Ministry of Science and Technology of China(2016YFC1305800).
文摘Background:Building brain reserves before dementia onset could represent a promising strategy to prevent Alzheimer’s disease(AD),while how to initiate early cognitive stimulation is unclear.Given that the immature brain is more sensitive to environmental stimuli and that brain dynamics decrease with ageing,we reasoned that it would be effective to initiate cognitive stimulation against AD as early as the fetal period.Methods:After conception,maternal AD transgenic mice(3×Tg AD)were exposed to gestational environment enrichment(GEE)until the day of delivery.The cognitive capacity of the offspring was assessed by the Morris water maze and contextual fear-conditioning tests when the offspring were raised in a standard environment to 7 months of age.Western blotting,immunohistochemistry,real-time PCR,immunoprecipitation,chromatin immunoprecipitation(ChIP)assay,electrophysiology,Golgi staining,activity assays and sandwich ELISA were employed to gain insight into the mechanisms underlying the beneficial effects of GEE on embryos and 7–10-month-old adult offspring.Results:We found that GEE markedly preserved synaptic plasticity and memory capacity with amelioration of hallmark pathologies in 7–10-m-old AD offspring.The beneficial effects of GEE were accompanied by global histone hyperacetylation,including those at bdnf promoter-binding regions,with robust BDNF mRNA and protein expression in both embryo and progeny hippocampus.GEE increased insulin-like growth factor 1(IGF1)and activated its receptor(IGF1R),which phosphorylates Ca^(2+)/calmodulin-dependent kinase IV(CaMKIV)at tyrosine sites and triggers its nuclear translocation,subsequently upregulating histone acetyltransferase(HAT)and BDNF transcription.The upregulation of IGF1 mimicked the effects of GEE,while IGF1R or HAT inhibition during pregnancy abolished the GEE-induced CaMKIV-dependent histone hyperacetylation and BDNF upregulation.Conclusions:These findings suggest that activation of IGF1R/CaMKIV/HAT/BDNF signaling by gestational environment enrichment may serve as a promising strategy to delay AD progression.
