Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been de...Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy(cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence(AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of mediumresolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.展开更多
Prostate cancer (PC) is one of the most common and leading cancer amongst the males all around the world. Depending upon it long latency and cost involved in its management and treatment, there is extensive need for m...Prostate cancer (PC) is one of the most common and leading cancer amongst the males all around the world. Depending upon it long latency and cost involved in its management and treatment, there is extensive need for more personalized and economical therapeutic approach for its effective therapy. The current review here discusses agents from natural dietary sources and drug class Non-Steroidal Antinflammatory (NSAIDS) that bears chemopreventive potential to regulate PC progression & tumour development and therefore could be devised into effective future treatment strategy against PC along with its metastatic castration-resistant form. Based on the literature search the therapeutic scope of selected agents are delineated, sighting their previous activity and prospects as epigenetic moderators in specific to particular PC causing biomarkers like over expression of AKR1C3, lost intracellular glutathione/glutathione-s-tranferases(GSH/GST) expression, DNA hypermethylation, aberrant cell proliferation and other related factors that are thought to potentiate and aggravate the onset of PC like smoking and use of other narcotics products.展开更多
Brain injuries due to trauma or stroke are major causes of adult death and disability.Unfortunately,few interventions are effective for post-injury repair of brain tissue.After a long debate on whether endogenous neur...Brain injuries due to trauma or stroke are major causes of adult death and disability.Unfortunately,few interventions are effective for post-injury repair of brain tissue.After a long debate on whether endogenous neurogenesis actually happens in the adult human brain,there is now substantial evidence to support its occurrence.Although neurogenesis is usually significantly stimulated by injury,the reparative potential of endogenous differentiation from neural stem/progenitor cells is usually insufficient.Alternatively,exogenous stem cell transplantation has shown promising results in animal models,but limitations such as poor long-term survival and inefficient neuronal differentiation make it still challenging for clinical use.Recently,a high focus was placed on glia-to-neuron conversion under single-factor regulation.Despite some inspiring results,the validity of this strategy is still controversial.In this review,we summarize historical findings and recent advances on neurogenesis strategies for neurorepair after brain injury.We also discuss their advantages and drawbacks,as to provide a comprehensive account of their potentials for further studies.展开更多
Retrograde adeno-associated viruses(AAVs)are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks.However,few retro-gr...Retrograde adeno-associated viruses(AAVs)are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks.However,few retro-grade AAV capsids have been shown to offer access to cor-tical projection neurons across different species and enable the manipulation of neural function in non-human primates(NHPs).Here,we report the development of a novel retro-grade AAV capsid,AAV-DJ8R,which efficiently labeled cortical projection neurons after local administration into the striatum of mice and macaques.In addition,intrastriatally injected AAV-DJ8R mediated opsin expression in the mouse motor cortex and induced robust behavioral alterations.Moreover,AAV-DJ8R markedly increased motor cortical neuron firing upon optogenetic light stimulation after viral delivery into the macaque putamen.These data demonstrate the usefulness of AAV-DJ8R as an efficient retrograde tracer for cortical projection neurons in rodents and NHPs and indicate its suitability for use in conducting functional interrogations.展开更多
Destruction of the blood-brain barrier is a critical component of epilepsy pathology.Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity.Howeve...Destruction of the blood-brain barrier is a critical component of epilepsy pathology.Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity.However,its effect on blood-brain barrier permeability in epileptic mice remains unclear.In this study,we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL/6 mice.S1P1 expression was increased in the hippocampus after status epilepticus,whereas tight junction protein expression was decreased in epileptic mice compared with controls.Intraperitoneal injection of SEW2871,a specific agonist of sphingosine-1-phosphate receptor 1,decreased the level of tight junction protein in the hippocampus of epileptic mice,increased blood-brain barrier leakage,and aggravated the severity of seizures compared with the control.W146,a specific antagonist of sphingosine-1-phosphate receptor 1,increased the level of tight junction protein,attenuated blood-brain barrier disruption,and reduced seizure severity compared with the control.Furthermore,sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1βand tumor necrosis factor-αand caused astrocytosis.Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline,a neuroinflammation inhibitor.Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors.Additionally,specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage,seizure severity,and epilepsy-associated depression-like behaviors.Taken together,our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.展开更多
Major depressive disorder(MDD)is a highly heterogeneous mental disorder,and its complex etiology and unclear mechanism are great obstacles to the diagnosis and treatment of the disease.Studies have shown that abnormal...Major depressive disorder(MDD)is a highly heterogeneous mental disorder,and its complex etiology and unclear mechanism are great obstacles to the diagnosis and treatment of the disease.Studies have shown that abnormal functions of the visual cortex have been reported in MDD patients,and the actions of several antidepressants coincide with improvements in the structure and synaptic functions of the visual cortex.In this review,we critically evaluate current evidence showing the involvement of the malfunctioning visual cortex in the pathophysiology and therapeutic process of depression.In addition,we discuss the molecular mechanisms of visual cortex dysfunction that may underlie the pathogenesis of MDD.Although the precise roles of visual cortex abnormalities in MDD remain uncertain,this undervalued brain region may become a novel area for the treatment of depressed patients.展开更多
Analyzing the complex structures and functions of brain is the key issue to understanding the physiological and pathological processes.Although neuronal morphology and local distribution of neurons/blood vessels in th...Analyzing the complex structures and functions of brain is the key issue to understanding the physiological and pathological processes.Although neuronal morphology and local distribution of neurons/blood vessels in the brain have been known,the subcellular structures of cells remain challenging,especially in the live brain.In addition,the complicated brain functions involve numerous functional molecules,but the concentrations,distributions and interactions of these molecules in the brain are still poorly understood.In this review,frontier techniques available for multiscale structure imaging from organelles to the whole brain are first overviewed,including magnetic resonance imaging(MRI),computed tomography(CT),positron emission tomography(PET),serial-section electron microscopy(ss EM),light microscopy(LM)and synchrotron-based X-ray microscopy(XRM).Specially,XRM for three-dimensional(3D)imaging of large-scale brain tissue with high resolution and fast imaging speed is highlighted.Additionally,the development of elegant methods for acquisition of brain functions from electrical/chemical signals in the brain is outlined.In particular,the new electrophysiology technologies for neural recordings at the single-neuron level and in the brain are also summarized.We also focus on the construction of electrochemical probes based on dual-recognition strategy and surface/interface chemistry for determination of chemical species in the brain with high selectivity and long-term stability,as well as electrochemophysiological microarray for simultaneously recording of electrochemical and electrophysiological signals in the brain.Moreover,the recent development of brain MRI probes with high contrast-to-noise ratio(CNR)and sensitivity based on hyperpolarized techniques and multi-nuclear chemistry is introduced.Furthermore,multiple optical probes and instruments,especially the optophysiological Raman probes and fiber Raman photometry,for imaging and biosensing in live brain are emphasized.Finally,a brief perspective on existing challenges and further research development is provided.展开更多
Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques,hyperphosphorylated tau protein,and neurofibrillar...Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques,hyperphosphorylated tau protein,and neurofibrillary tangles in the brain.The overexpression of amyloid-βprecursor protein(APP)in an AD brain results in the binding of APP intracellular domain(AICD)to Fe65 protein via the C-terminal Fe65-PTB2 interaction,which then triggers the secretion of amyloid-βand the consequent pathogenesis of AD.Apparently,targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD.Recently,exosome,a type of extracellular vesicle with diameter around 30–200 nm,has gained much attention as a potential delivery tool for brain diseases,including AD,due to their ability to cross the blood–brain barrier,their efficient uptake by autologous cells,and their ability to be surface-modified with target-specific receptor ligands.Here,the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65,enabled the development of a novel exosome-based targeted drug delivery system,which carried Corynoxine-B(Cory-B,an autophagy inducer)to the APP overexpressed-neuron cells in the brain of AD mice.The Fe65-engineered HT22 hippocampus neuron cell-derived exosomes(Fe65-EXO)loaded with Cory-B(Fe65-EXO-Cory-B)hijacked the signaling and blocked the natural interaction between Fe65 and APP,enabling APP-targeted delivery of Cory-B.Notably,Fe65-EXO-Cory-B induced autophagy in APP-expressing neuronal cells,leading to amelioration of the cognitive decline and pathogenesis in AD mice,demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD.展开更多
The widespread applications of aggregation-induced emission luminogens(AIEgens)inspire the creation of AIEgens with novel structures and functionalities.In this work,we focused on the direct and efficient synthesis of...The widespread applications of aggregation-induced emission luminogens(AIEgens)inspire the creation of AIEgens with novel structures and functionalities.In this work,we focused on the direct and efficient synthesis of a new type of AIEgens,imidazo[1,5-a]pyridicne derivatives,via iodine mediated cascade oxidative Csp^(2)–H or Csp–H amination route from phenylacetylene or styrenes under mild conditions.The resulted compounds showed excellent AIE characteristics with tunable maximum emissions,attractive bioimaging performance,and potential anti-inflammatory activity,which exert broad application prospects in material,biology,medicine,and other relevant areas.展开更多
Superparamagnetic iron oxide(SPIO)nanoparticles play an important role in mediating precise and effective magnetic neurostimulation and can help overcome limitations related to penetration depth and spatial resolution...Superparamagnetic iron oxide(SPIO)nanoparticles play an important role in mediating precise and effective magnetic neurostimulation and can help overcome limitations related to penetration depth and spatial resolution.However,nanoparticles readily diffuse in vivo,decreasing the spatial resolution and activation efficiency.In this study,we employed a microfluidic means to fabricate injectable microhydrogels encapsulated with SPIO nanoparticles,which significantly improved the stability of nanoparticles,increased the magnetic properties,reinforced the stimulation effectivity.The fabricated magnetic microhydrogels were highly uniform in size and sphericity,enabling minimally invasive injection into brain tissue.The long-term residency in the cortex up to 22 weeks and the safety of brain tissue were shown using a mouse model.In addition,we quantitatively determined the magneto-mechanical force yielded by only one magnetic microhydrogel using a video-based method.The force was found to be within 7–8 pN under 10 Hz magnetic stimulation by both theoretical simulation and experimental measurement.Lastly,electrophysiological measurement of brain slices showed that the magnetic microhydrogels offer significant advantages in terms of neural activation relative to dissociative SPIO nanoparticles.A universal strategy is thus offered for performing magnetic neuro-stimulation with an improved prospect for biomedical translation.展开更多
Dear Editor,Alzheimer's disease(AD)is one of the most devastating neurodegenerative disorders and the most common form of dementia.Synaptic loss is a hallmark of AD pathology and exacerbates cognitive impairment[1...Dear Editor,Alzheimer's disease(AD)is one of the most devastating neurodegenerative disorders and the most common form of dementia.Synaptic loss is a hallmark of AD pathology and exacerbates cognitive impairment[1].Synaptic loss,unlike neuronal loss,is reversible due to the highly dynamic properties of synapses.展开更多
Alzheimer’s disease(AD)is the most common type of dementia.Almost two-thirds of patients with AD are female.The reason for the higher susceptibility to AD onset in women is unclear.However,hormone changes during the ...Alzheimer’s disease(AD)is the most common type of dementia.Almost two-thirds of patients with AD are female.The reason for the higher susceptibility to AD onset in women is unclear.However,hormone changes during the menopausal transition are known to be associated with AD.Most recently,we reported that follicle-stimulating hormone(FSH)promotes AD pathology and enhances cognitive dysfunctions via activating the CCAAT-enhancer-binding protein(C/EBPβ)/asparagine endopeptidase(AEP)pathway.This review summarizes our current understanding of the crucial role of the C/EBPβ/AEP pathway in driving AD pathogenesis by cleaving multiple critical AD players,including APP and Tau,explaining the roles and the mechanisms of FSH in increasing the susceptibility to AD in postmenopausal females.The FSH-C/EBPβ/AEP pathway may serve as a novel therapeutic target for the treatment of AD.展开更多
No well-established biomarkers are available for the clinical diagnosis of major depressive disorder(MDD).Vitamin D-binding protein(VDBP)is altered in plasma and postmortem dorsolateral prefrontal cortex(DLPFC)tissues...No well-established biomarkers are available for the clinical diagnosis of major depressive disorder(MDD).Vitamin D-binding protein(VDBP)is altered in plasma and postmortem dorsolateral prefrontal cortex(DLPFC)tissues of MDD patients.Thereby,the role of VDBP as a potential biomarker of MDD diagnosis was further assessed.Total extracellular vesicles(EVs)and brain cell-derived EVs(BCDEVs)were isolated from the plasma of first-episode drug-naïve or drug-free MDD patients and well-matched healthy controls(HCs)in discovery(20 MDD patients and 20 HCs)and validation cohorts(88 MDD patients and 38 HCs).VDBP level in the cerebrospinal fluid(CSF)from chronic glucocorticoid-induced depressed rhesus macaques or prelimbic cortex from lipopolysaccharide(LPS)-induced depressed mice and wild control groups was measured to evaluate its relationship with VDBP in plasma microglia-derived extracellular vesicles(MDEVs).VDBP was significantly decreased in MDD plasma MDEVs compared to HCs,and negatively correlated with HAMD-24 score with the highest diagnostic accuracy among BCDEVs.VDBP in plasma MDEVs was decreased both in depressed rhesus macaques and mice.A positive correlation of VDBP in MDEVs with that in CSF was detected in depressed rhesus macaques.VDBP levels in prelimbic cortex microglia were negatively correlated with those in plasma MDEVs in depressed mice.The main results suggested that VDBP in plasma MDEVs might serve as a prospective candidate biomarker for MDD diagnosis.展开更多
The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a s...The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.展开更多
基金funded by the National Natural Science Foundation of China (NSFC, 31900046, 81972085, 82172465 and 32161133022)the Guangdong Provincial Key Laboratory of Advanced Biomaterials (2022B1212010003)+7 种基金the National Science and Technology Innovation 2030 Major Program (2022ZD0211900)the Shenzhen Key Laboratory of Computer Aided Drug Discovery (ZDSYS20201230165400001)the Chinese Academy of Science President’s International Fellowship Initiative (PIFI)(2020FSB0003)the Guangdong Retired Expert (granted by Guangdong Province)the Shenzhen Pengcheng ScientistNSFC-SNSF Funding (32161133022)Alpha Mol&SIAT Joint LaboratoryShenzhen Government Top-talent Working Funding and Guangdong Province Academician Work Funding。
文摘Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy(cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence(AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of mediumresolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.
文摘Prostate cancer (PC) is one of the most common and leading cancer amongst the males all around the world. Depending upon it long latency and cost involved in its management and treatment, there is extensive need for more personalized and economical therapeutic approach for its effective therapy. The current review here discusses agents from natural dietary sources and drug class Non-Steroidal Antinflammatory (NSAIDS) that bears chemopreventive potential to regulate PC progression & tumour development and therefore could be devised into effective future treatment strategy against PC along with its metastatic castration-resistant form. Based on the literature search the therapeutic scope of selected agents are delineated, sighting their previous activity and prospects as epigenetic moderators in specific to particular PC causing biomarkers like over expression of AKR1C3, lost intracellular glutathione/glutathione-s-tranferases(GSH/GST) expression, DNA hypermethylation, aberrant cell proliferation and other related factors that are thought to potentiate and aggravate the onset of PC like smoking and use of other narcotics products.
基金supported by the SIAT Innovation Program for Excellent Young Researchers,No.E1G0241001(to XZ)。
文摘Brain injuries due to trauma or stroke are major causes of adult death and disability.Unfortunately,few interventions are effective for post-injury repair of brain tissue.After a long debate on whether endogenous neurogenesis actually happens in the adult human brain,there is now substantial evidence to support its occurrence.Although neurogenesis is usually significantly stimulated by injury,the reparative potential of endogenous differentiation from neural stem/progenitor cells is usually insufficient.Alternatively,exogenous stem cell transplantation has shown promising results in animal models,but limitations such as poor long-term survival and inefficient neuronal differentiation make it still challenging for clinical use.Recently,a high focus was placed on glia-to-neuron conversion under single-factor regulation.Despite some inspiring results,the validity of this strategy is still controversial.In this review,we summarize historical findings and recent advances on neurogenesis strategies for neurorepair after brain injury.We also discuss their advantages and drawbacks,as to provide a comprehensive account of their potentials for further studies.
基金supported by Ministry of Science and Technology of China(2019YFA0903803 and 2018YFA0801404)National Natural Science Foundation of China(31871090,32000730,81961128019,and 81901397)+7 种基金Shenzhen Science and Technology Innovation Commission(JCYJ20190809171003698,JCYJ202103243001018,JCYJ20180507182505475,and JCYJ20180504165804015)Shenzhen Technological Research Center for Primate Translational Medicine(F-2021-Z99-504979)Youth Innovation Promotion Association(CAS 2017120)Chinese Academy of Sciences International Partnership Program(172644KYSB20170004)China Postdoctoral Science Foundation(2019M653115.)CAS Key Laboratory of Brain Connectome and Manipulation(2019DP173024)Guangdong Provincial Key Laboratory of Brain Connectome and Behavior(2017B030301017)International Science and Technology Cooperation Base of Guangdong Province(2019A050505008).
文摘Retrograde adeno-associated viruses(AAVs)are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks.However,few retro-grade AAV capsids have been shown to offer access to cor-tical projection neurons across different species and enable the manipulation of neural function in non-human primates(NHPs).Here,we report the development of a novel retro-grade AAV capsid,AAV-DJ8R,which efficiently labeled cortical projection neurons after local administration into the striatum of mice and macaques.In addition,intrastriatally injected AAV-DJ8R mediated opsin expression in the mouse motor cortex and induced robust behavioral alterations.Moreover,AAV-DJ8R markedly increased motor cortical neuron firing upon optogenetic light stimulation after viral delivery into the macaque putamen.These data demonstrate the usefulness of AAV-DJ8R as an efficient retrograde tracer for cortical projection neurons in rodents and NHPs and indicate its suitability for use in conducting functional interrogations.
基金supported by the National Natural Science Foundation of China,Nos.82071393(to HLC),81830040(to ZJZ),82130042(to ZJZ)Science and Technology Program of Guangdong Province,No.2018B030334001(to ZJZ)the Program of Excellent Talents in Medical Science of Jiangsu Province,No.JCRCA2016006(to ZJZ)。
文摘Destruction of the blood-brain barrier is a critical component of epilepsy pathology.Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity.However,its effect on blood-brain barrier permeability in epileptic mice remains unclear.In this study,we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL/6 mice.S1P1 expression was increased in the hippocampus after status epilepticus,whereas tight junction protein expression was decreased in epileptic mice compared with controls.Intraperitoneal injection of SEW2871,a specific agonist of sphingosine-1-phosphate receptor 1,decreased the level of tight junction protein in the hippocampus of epileptic mice,increased blood-brain barrier leakage,and aggravated the severity of seizures compared with the control.W146,a specific antagonist of sphingosine-1-phosphate receptor 1,increased the level of tight junction protein,attenuated blood-brain barrier disruption,and reduced seizure severity compared with the control.Furthermore,sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1βand tumor necrosis factor-αand caused astrocytosis.Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline,a neuroinflammation inhibitor.Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors.Additionally,specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage,seizure severity,and epilepsy-associated depression-like behaviors.Taken together,our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.
基金This review was supported by grants from the National Natural Science Key Foundation of China(81830040 and 82130042)the China Science and Technology Innovation 2030-Major Project(2022ZD0211701 and 2021ZD0200700)+1 种基金the Science and Technology Program of Guangdong(2018B030334001)the Science and Technology Program of Shenzhen(GJHZ20210705141400002,KCXFZ20211020164543006,JCYJ20220818101615033,and 202206063000055).
文摘Major depressive disorder(MDD)is a highly heterogeneous mental disorder,and its complex etiology and unclear mechanism are great obstacles to the diagnosis and treatment of the disease.Studies have shown that abnormal functions of the visual cortex have been reported in MDD patients,and the actions of several antidepressants coincide with improvements in the structure and synaptic functions of the visual cortex.In this review,we critically evaluate current evidence showing the involvement of the malfunctioning visual cortex in the pathophysiology and therapeutic process of depression.In addition,we discuss the molecular mechanisms of visual cortex dysfunction that may underlie the pathogenesis of MDD.Although the precise roles of visual cortex abnormalities in MDD remain uncertain,this undervalued brain region may become a novel area for the treatment of depressed patients.
基金supported by the National Natural Science Foundation of China(22004037 for Liu Z22022410 and 82050005 for Zhu Y+9 种基金22022402 and 21974051 for Zhang L21635003 and21811540027 for Tian Y22125701 and 21834007 for Liu K22020102003for Zhang H91859206 and 21921004 for Zhou X)the Innovation Program of Shanghai Municipal Education Commission(201701070005E00020 for Tian Y)the Research Funds of Happiness Flower ECNU(2020JK2103 for Tian Y)the Shanghai Municipal Science and Technology Commission(19JC1410300 for Fan C)the Youth Innovation Promotion Association of CAS(2016236 for Zhu Y)the National Key Research and Development Project of China(2018YFA0704000 for Zhou X)。
文摘Analyzing the complex structures and functions of brain is the key issue to understanding the physiological and pathological processes.Although neuronal morphology and local distribution of neurons/blood vessels in the brain have been known,the subcellular structures of cells remain challenging,especially in the live brain.In addition,the complicated brain functions involve numerous functional molecules,but the concentrations,distributions and interactions of these molecules in the brain are still poorly understood.In this review,frontier techniques available for multiscale structure imaging from organelles to the whole brain are first overviewed,including magnetic resonance imaging(MRI),computed tomography(CT),positron emission tomography(PET),serial-section electron microscopy(ss EM),light microscopy(LM)and synchrotron-based X-ray microscopy(XRM).Specially,XRM for three-dimensional(3D)imaging of large-scale brain tissue with high resolution and fast imaging speed is highlighted.Additionally,the development of elegant methods for acquisition of brain functions from electrical/chemical signals in the brain is outlined.In particular,the new electrophysiology technologies for neural recordings at the single-neuron level and in the brain are also summarized.We also focus on the construction of electrochemical probes based on dual-recognition strategy and surface/interface chemistry for determination of chemical species in the brain with high selectivity and long-term stability,as well as electrochemophysiological microarray for simultaneously recording of electrochemical and electrophysiological signals in the brain.Moreover,the recent development of brain MRI probes with high contrast-to-noise ratio(CNR)and sensitivity based on hyperpolarized techniques and multi-nuclear chemistry is introduced.Furthermore,multiple optical probes and instruments,especially the optophysiological Raman probes and fiber Raman photometry,for imaging and biosensing in live brain are emphasized.Finally,a brief perspective on existing challenges and further research development is provided.
基金the grants of Health and Medical Research Fund HMRF/17182541(ML)Health and Medical Research Fund HMRF/17182551(AlI)+10 种基金Matching Proof-of-Concept Fund(MPCF)HKBU-MPCF-003-2022-23(AI)Health and Medical Research Fund HMRF/09203776(ML)Research Grants Council of Hong Kong,General Research Fund GRF/2100618(ML)Research Grants Council of Hong Kong,General Research Fund GRF/12101022(ML)Research Grants Council of Hong Kong,Collaborative Research Fund C2011-21GF(ML)Hong Kong Baptist University Grant HKBU/RC-IRCs/17-18/03(ML)Hong Kong Baptist University Grant IRCMS/19-20/H02(ML,Al)U.S.National Institute of Health,NCI R00 CA226353-01A1(HJC)U.S.National Institute of Health,NCI K99 CA226353-01A1(HJC)Cancer Research Foundation Young Investigator Award(HJC)LCRF pilot grant(HJC).
文摘Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques,hyperphosphorylated tau protein,and neurofibrillary tangles in the brain.The overexpression of amyloid-βprecursor protein(APP)in an AD brain results in the binding of APP intracellular domain(AICD)to Fe65 protein via the C-terminal Fe65-PTB2 interaction,which then triggers the secretion of amyloid-βand the consequent pathogenesis of AD.Apparently,targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD.Recently,exosome,a type of extracellular vesicle with diameter around 30–200 nm,has gained much attention as a potential delivery tool for brain diseases,including AD,due to their ability to cross the blood–brain barrier,their efficient uptake by autologous cells,and their ability to be surface-modified with target-specific receptor ligands.Here,the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65,enabled the development of a novel exosome-based targeted drug delivery system,which carried Corynoxine-B(Cory-B,an autophagy inducer)to the APP overexpressed-neuron cells in the brain of AD mice.The Fe65-engineered HT22 hippocampus neuron cell-derived exosomes(Fe65-EXO)loaded with Cory-B(Fe65-EXO-Cory-B)hijacked the signaling and blocked the natural interaction between Fe65 and APP,enabling APP-targeted delivery of Cory-B.Notably,Fe65-EXO-Cory-B induced autophagy in APP-expressing neuronal cells,leading to amelioration of the cognitive decline and pathogenesis in AD mice,demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD.
基金financially supported by the National Natural Science Foundation of China(Nos.22077099,21807087and 21673173)Key Research and Development Plan in Shaanxi Province of China(No.2019KWZ-07)+2 种基金the Technology Innovation Leading Program of Shaanxi(No.2020TG-031)the Xi’an CityScience and Technology Project(Nos.2019218214GXRC018CG019-GXYD18.4 and 2020KJRC0115)the support from COVID-19 Prophylaxis and Treatment Emergency Research Special Projects of Northwest University。
文摘The widespread applications of aggregation-induced emission luminogens(AIEgens)inspire the creation of AIEgens with novel structures and functionalities.In this work,we focused on the direct and efficient synthesis of a new type of AIEgens,imidazo[1,5-a]pyridicne derivatives,via iodine mediated cascade oxidative Csp^(2)–H or Csp–H amination route from phenylacetylene or styrenes under mild conditions.The resulted compounds showed excellent AIE characteristics with tunable maximum emissions,attractive bioimaging performance,and potential anti-inflammatory activity,which exert broad application prospects in material,biology,medicine,and other relevant areas.
基金the National Key Research and Development Program of China(No.2021YFA1201403 to J.F.S.)China Science and Technology Innovation 2030-Major Project(Nos.2022ZD0211701 to Z.J.Z.and 2022ZD0211704 to J.F.S.)+2 种基金the National Natural Science Key Foundation of China(Nos.81830040 and 82130042 to Z.J.Z.)the Science and Technology Program of Guangdong(No.2018B030334001 to Z.J.Z.)the Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.SJCX21_0146 to L.X.).
文摘Superparamagnetic iron oxide(SPIO)nanoparticles play an important role in mediating precise and effective magnetic neurostimulation and can help overcome limitations related to penetration depth and spatial resolution.However,nanoparticles readily diffuse in vivo,decreasing the spatial resolution and activation efficiency.In this study,we employed a microfluidic means to fabricate injectable microhydrogels encapsulated with SPIO nanoparticles,which significantly improved the stability of nanoparticles,increased the magnetic properties,reinforced the stimulation effectivity.The fabricated magnetic microhydrogels were highly uniform in size and sphericity,enabling minimally invasive injection into brain tissue.The long-term residency in the cortex up to 22 weeks and the safety of brain tissue were shown using a mouse model.In addition,we quantitatively determined the magneto-mechanical force yielded by only one magnetic microhydrogel using a video-based method.The force was found to be within 7–8 pN under 10 Hz magnetic stimulation by both theoretical simulation and experimental measurement.Lastly,electrophysiological measurement of brain slices showed that the magnetic microhydrogels offer significant advantages in terms of neural activation relative to dissociative SPIO nanoparticles.A universal strategy is thus offered for performing magnetic neuro-stimulation with an improved prospect for biomedical translation.
基金the Frontier Research Program of Biol and Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory)(2018GZR110105006)the National Natural ScienceFoundation of China(31900735,82171492,and 81922024)the Science,Technology and Innovation Commission of Shenzhen Municipality(RCJC 20200714114556103 and ZDSYS20190902093601675).
文摘Dear Editor,Alzheimer's disease(AD)is one of the most devastating neurodegenerative disorders and the most common form of dementia.Synaptic loss is a hallmark of AD pathology and exacerbates cognitive impairment[1].Synaptic loss,unlike neuronal loss,is reversible due to the highly dynamic properties of synapses.
基金supported by start-up funding from Shenzhen Institute of Advanced Technologythe National Natural Science Foundation of China(No.82271446).
文摘Alzheimer’s disease(AD)is the most common type of dementia.Almost two-thirds of patients with AD are female.The reason for the higher susceptibility to AD onset in women is unclear.However,hormone changes during the menopausal transition are known to be associated with AD.Most recently,we reported that follicle-stimulating hormone(FSH)promotes AD pathology and enhances cognitive dysfunctions via activating the CCAAT-enhancer-binding protein(C/EBPβ)/asparagine endopeptidase(AEP)pathway.This review summarizes our current understanding of the crucial role of the C/EBPβ/AEP pathway in driving AD pathogenesis by cleaving multiple critical AD players,including APP and Tau,explaining the roles and the mechanisms of FSH in increasing the susceptibility to AD in postmenopausal females.The FSH-C/EBPβ/AEP pathway may serve as a novel therapeutic target for the treatment of AD.
基金supported by the National Natural Science Key Foundation of China(No.81830040 and 82130042 to ZJ Zhang)China Science and Technology Innovation 2030-Major Project(China)(No.2022ZD0211701,2022ZD0211700 and 2021ZD0200700 to ZJ Zhang)+2 种基金Science and Technology Program of Guangdong,China(No.2018B030334001 to ZJ Zhang)Science and Technology Program of Shenzhen,China(No.GJHZ20210705141400002,KCXFZ20211020164543006,JCYJ20220818101615033 and ZDSYS20220606100606014 to ZJ Zhang)The National Natural Science Foundation of China(No.U20A6005 to ZQM).
文摘No well-established biomarkers are available for the clinical diagnosis of major depressive disorder(MDD).Vitamin D-binding protein(VDBP)is altered in plasma and postmortem dorsolateral prefrontal cortex(DLPFC)tissues of MDD patients.Thereby,the role of VDBP as a potential biomarker of MDD diagnosis was further assessed.Total extracellular vesicles(EVs)and brain cell-derived EVs(BCDEVs)were isolated from the plasma of first-episode drug-naïve or drug-free MDD patients and well-matched healthy controls(HCs)in discovery(20 MDD patients and 20 HCs)and validation cohorts(88 MDD patients and 38 HCs).VDBP level in the cerebrospinal fluid(CSF)from chronic glucocorticoid-induced depressed rhesus macaques or prelimbic cortex from lipopolysaccharide(LPS)-induced depressed mice and wild control groups was measured to evaluate its relationship with VDBP in plasma microglia-derived extracellular vesicles(MDEVs).VDBP was significantly decreased in MDD plasma MDEVs compared to HCs,and negatively correlated with HAMD-24 score with the highest diagnostic accuracy among BCDEVs.VDBP in plasma MDEVs was decreased both in depressed rhesus macaques and mice.A positive correlation of VDBP in MDEVs with that in CSF was detected in depressed rhesus macaques.VDBP levels in prelimbic cortex microglia were negatively correlated with those in plasma MDEVs in depressed mice.The main results suggested that VDBP in plasma MDEVs might serve as a prospective candidate biomarker for MDD diagnosis.
基金National Natural Science Foundation of China,Grant/Award Numbers:92249305,82120108010,81930028,31921003Academy of Medical Sciences(Newton Advanced Fellowship),Grant/Award Number:NAF/R11/1010National Institutes of Health,Grant/Award Number:R01DA056739。
文摘The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.
