Alzheimer’s disease is a progressive and fatal neurodegenerative disorder that starts many years before the onset of cognitive symptoms.Identifying novel biomarkers for Alzheimer’s disease has the potential for pati...Alzheimer’s disease is a progressive and fatal neurodegenerative disorder that starts many years before the onset of cognitive symptoms.Identifying novel biomarkers for Alzheimer’s disease has the potential for patient risk stratification,early diagnosis,and disease monitoring in response to therapy.A novel class of biomarkers is extracellular vesicles given their sensitivity and specificity to specific diseases.In addition,extracellular vesicles can be used as novel biological therapeutics given their ability to efficiently and functionally deliver therapeutic cargo.This is critical given the huge unmet need for novel treatment strategies for Alzheimer’s disease.This review summarizes and discusses the most recent findings in this field.展开更多
The most prevalent form of dementia in the elderly is Alzheimer's disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42(Aβ42),a smal...The most prevalent form of dementia in the elderly is Alzheimer's disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42(Aβ42),a small hydrophobic peptide.Unfortunately,attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease.It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach.The accumulation of Aβ42 seems to affect various aspects of physiological cell functions.In this review,we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction,with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release.We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer's disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease.Although the precise mechanisms that trigger synaptic dysfunction are still under investigation,the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.展开更多
Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheime...Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.展开更多
Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt)...Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.展开更多
Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism....Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.展开更多
INTRODUCTION Our previous study has proved that Kupffer cellsmay have an inhibitory effect on the process ofhepatocarcinogenesis,however,their inhibitorymechanism needs exploring deeply.We performed acomparative study...INTRODUCTION Our previous study has proved that Kupffer cellsmay have an inhibitory effect on the process ofhepatocarcinogenesis,however,their inhibitorymechanism needs exploring deeply.We performed acomparative study on the expression of PCNA,Bax,P53 and apoptosis of liver cancer cells usingimmunohistochemical technology and terminaldeoxynucleotidyl transferase (TdT)-mediateddUTP-digoxigenin nick end labeling(TUNEL)展开更多
Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchyma...Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241(EVs-AM1241)to protect against neurodegenerative progression and neuronal function in AD model mice.According to the results,EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241.The Morris water maze(MWM)and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved.In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning.Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloidβ(Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241.Moreover,EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton,indicating that they enhanced neuronal regeneration.RNA sequencing revealed that EVs-AM1241 facilitated Aβphagocytosis,promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway.Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in modelmice,indicating that they are very promising particles for treating AD.展开更多
In the last decades,the role of the prion protein(PrP) in neurodegenerative diseases has been intensively investigated,initially in prion diseases of humans(e.g., Creutzfeldt-J akob disease) and animals(e.g.,scrapie i...In the last decades,the role of the prion protein(PrP) in neurodegenerative diseases has been intensively investigated,initially in prion diseases of humans(e.g., Creutzfeldt-J akob disease) and animals(e.g.,scrapie in sheep,chronic wasting disease in deer and elk,or "mad cow disease" in cattle).Templated misfolding of physiological cellular prion protein(PrPC) into an aggregation-prone isoform(termed PrP "Scrapie"(PrPSc)),self-re plication and spreading of the latter inside the brain and to peripheral tissues,and the associated formation of infectious proteopathic seeds(termed "prions")are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies.Late r,key roles of the correctly folded PrPCwere identified in more common human brain diseases(such as Alzheimer s disease or Parkinson’s disease) associated with the misfolding and/or accumulation of other proteins(such as amyloid-β,tau or α-synuclein,respectively).PrPChas also been linked with n euro protective and regenerative functions,for instance in hypoxic/ischemic conditions such as stroke.However,despite a mixed "bouquet" of suggested functions,our understanding of pathological and,especially,physiological roles played by PrPCin the brain and beyond is ce rtainly incomplete.Interactions with various other proteins at the cell surfa ce or within intracellular compartments may account for the functional diversity linked with PrPC.Moreover,conserved endogenous proteolytic processing of PrPCgenerates seve ral defined PrPCfragments,possibly holding intrinsic functions in physiological and pathological conditions,thus making the "true and complete biology" of this protein more complicated to be elucidated.Here,we focus on one of those released PrPCfragments,namely shed PrP(sPrP),generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surfa ce.Similar to other soluble PrP fragments(such as the N1 fragment representing PrP’s released N-terminal tail upon the major α-cleavage event)or expe rimentally employed recombinant PrP,sPrP is being suggested to act n euro protective in Alzheimer’s disease and other protein misfolding diseases.Seve ral lines of evidence on extracellular PrPC(fragments) suggest that induction of PrPCrelease co uld be a future therapeutic option in various brain disorders.Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM 10,based on ligands binding to cell surface PrPC,may further set the stage for research into this direction.展开更多
Fish embryos are widely used as models in toxicology,drug development,and human disease research because of their high sensitivity,observability,and operability,providing the basis for an in-depth understanding of the...Fish embryos are widely used as models in toxicology,drug development,and human disease research because of their high sensitivity,observability,and operability,providing the basis for an in-depth understanding of the embryogenesis.Increasing studies have indicated that birth defects are hereditary.In this study,we used Oryzias melastigma as a model to conduct a study of 185-day embryogenesis and observed self-induced non-pathological abnormal embryogenesis.O.melastigma experienced pre-puberty stage,adolescence stage,and senescence stage,and individuals produced up to 102 eggs per day.However,the fecundity was markedly reduced during the senescent stage.During the active egg and blastodisc stages,pseudo-fertilization and pseudo-blastocysts were observed.During cleavage at the 4-to 32-cell stages,we observed blastomeres separation or dislocation.Excessively separated blastomeres formed double blastoderms,eventually resulting in conjoined twins.During the blastula stage,we observed abnormally increased cell volume,narrowed and elongated blastocysts,and abnormally coated blastoderms.At the organogenesis stage,we observed abnormal numbers of Kupff er’s vesicles and conjoined twins.Abnormality in the location and number of oil droplets were observed in various development stages.Abnormal development was more commonly observed in fertilized eggs produced by broodstock in pre-puberty or senescence stages,which is probably related to the age of fish and the egg quality.This study can provide the materials for comparative analysis in toxicological and molecular studies of O.melastigma,and may provide evidence for other economic fish that produce sticky eggs.展开更多
Zinner syndrome is a rare congenital malformation related to an abnormality in the development of the Wolffian duct, the clinical picture of which consists of a triad of unilateral renal agenesis, ipsilateral seminal ...Zinner syndrome is a rare congenital malformation related to an abnormality in the development of the Wolffian duct, the clinical picture of which consists of a triad of unilateral renal agenesis, ipsilateral seminal vesicle cyst, and obstruction of the ejaculatory duct. Chronic perineoscrotal pain may be an indication of the diagnosis of Z<span style="white-space:nowrap;">ï</span>nner syndrome to some extent. We report the observation of a 23-year-old patient, married and father of one child, who presented with chronic perineo-scrotal pain revealing on morphological assessment (ultrasound, uroscanner, prostatic MRI) a cystic formation of the seminal vesicle, left renal agenesis with an empty left renal compartment. Given the patient’s refusal of any surgical procedure, treatment consisted of echo-guided puncture of the seminal vesicle cyst bringing back 30 cc of a seroviscous liquid whose analysis revealed spermatozoa, without atypical cells, compatible with a cyst. The clinical evolution was marked by a progressive remission of the scrotal pain with a delay of several months.展开更多
Redox responsive vesicles were constructed based on guest interaction between fl-cyclodextrin and a ferrocene self-assembly of a supra-amphiphile built by the host- derivative. The structure and destruction-reconstruc...Redox responsive vesicles were constructed based on guest interaction between fl-cyclodextrin and a ferrocene self-assembly of a supra-amphiphile built by the host- derivative. The structure and destruction-reconstruction reversibility of the "smart" vesicles were clearly characterized by electron microscopy and dynamic light scattering. Notably, these vesicles were proved to be capable of controlled release function and bringing protease resistance to the enzyme, showing great biocompatibility and promising applications.展开更多
Background:Blood-based test for predicting disease progression and early diagnosis of Parkinson’s disease(PD)is an unmet need in the clinic.The profiles of microRNAs(miRNAs)are regarded as potential diagnostic biomar...Background:Blood-based test for predicting disease progression and early diagnosis of Parkinson’s disease(PD)is an unmet need in the clinic.The profiles of microRNAs(miRNAs)are regarded as potential diagnostic biomarkers for human diseases,whereas miRNAs in the periphery are susceptible to the influence of various components.MiRNAs enriched in serum extracellular vesicles(EVs)have demonstrated disease-specific advantages in diagnosis due to their high abundance,stability and resistance to degradation.This study was aimed to screen differentially expressed EV-derived miRNAs between healthy controls and PD patients to aid in diagnosis of PD.Methods:A total of 31 healthy controls and 72 patients with a diagnosis of PD at different Hoehn and Yahr stages in Tangdu Hospital were included.In total,185 differentially expressed miRNAs were obtained through RNA sequencing of serum EVs as well as edgeR and t-test analyses.Subsequently,the weighted gene co-expression network analysis(WGCNA)was utilized to identify the commonly expressed miRNAs in all stages of PD by constructing connections between modules,and specifically expressed miRNAs in each stage of PD by functional enrichment analysis.After aligning these miRNAs with PD-related miRNAs in Human miRNA Disease Database,the screened miRNAs were further validated by receiver operating characteristic(ROC)curves and quantitative real-time polymerase chain reaction(qRT-PCR)using peripheral blood EVs from 40 more participants.Results:WGCNA showed that 4 miRNAs were commonly associated with all stages of PD and 13 miRNAs were specifically associated with different stages of PD.Of the 17 obtained miRNAs,7 were validated by ROC curve analysis and 7 were verified in 40 more participants by qRT-PCR.Six miRNAs were verified by both methods,which included 2 miRNAs that were commonly expressed in all stages of PD and 4 miRNAs that were specifically expressed in different stages of PD.Conclusions:The 6 serum EV-derived miRNAs,hsa-miR-374a-5p,hsa-miR-374b-5p,hsa-miR-199a-3p,hsa-miR-28-5p,hsa-miR-22-5p and hsa-miR-151a-5p,may potentially be used as biomarkers for PD progression and for early diagnosis of PD in populations.展开更多
Background:We recently demonstrated an endolysosomal accumulation of theβ-secretase-derived APP C-terminal fragment(CTF)C99 in brains of Alzheimer disease(AD)mouse models.Moreover,we showed that the treatment with th...Background:We recently demonstrated an endolysosomal accumulation of theβ-secretase-derived APP C-terminal fragment(CTF)C99 in brains of Alzheimer disease(AD)mouse models.Moreover,we showed that the treatment with theγ-secretase inhibitor(D6)led to further increased endolysosomal APP-CTF levels,but also revealed extracellular APP-CTF-associated immunostaining.We here hypothesized that this latter staining could reflect extracellular vesicle(EV)-associated APP-CTFs and aimed to characterize theseγ-secretase inhibitor-induced APPCTFs.Methods:EVs were purified from cell media or mouse brains from vehicle-or D6-treated C99 or APPswedish expressing cells/mice and analyzed for APP-CTFs by immunoblot.Combined pharmacological,immunological and genetic approaches(presenilin invalidation and C99 dimerization mutants(GXXXG))were used to characterize vesicle-containing APP-CTFs.Subcellular APP-CTF localization was determined by immunocytochemistry.Results:Purified EVs from both AD cell or mouse models were enriched in APP-CTFs as compared to EVs from control cells/brains.Surprisingly,EVs from D6-treated cells not only displayed increased C99 and C99-derived C83 levels but also higher molecular weight(HMW)APP-CTF-immunoreactivities that were hardly detectable in whole cell extracts.Accordingly,the intracellular levels of HMW APP-CTFs were amplified by the exosomal inhibitor GW4869.By combined pharmacological,immunological and genetic approaches,we established that these HMW APP-CTFs correspond to oligomeric APP-CTFs composed of C99 and/or C83.Immunocytochemical analysis showed that monomers were localized mainly to the trans-Golgi network,whereas oligomers were confined to endosomes and lysosomes,thus providing an anatomical support for the selective recovery of HMW APP-CTFs in EVs.The D6-induced APP-CTF oligomerization and subcellular mislocalization was indeed due toγ-secretase blockade,since it similarly occurred in presenilin-deficient fibroblasts.Further,our data proposed that besides favoring APP-CTF oligomerization by preventing C99 proteolysis,γ-secretase inhibiton also led to a defective SorLA-mediated retrograde transport of HMW APP-CTFs from endosomal compartments to the TGN.Conclusions:This is the first study to demonstrate the presence of oligomeric APP-CTFs in AD mouse models,the levels of which are selectively enriched in endolysosomal compartments including exosomes and amplified byγ-secretase inhibition.Future studies should evaluate the putative contribution of these exosome-associated APP-CTFs in AD onset,progression and spreading.展开更多
In this survey article,we present two applications of surface curvatures in theoretical physics.The first application arises from biophysics in the study of the shape of cell vesicles involving the minimization of a m...In this survey article,we present two applications of surface curvatures in theoretical physics.The first application arises from biophysics in the study of the shape of cell vesicles involving the minimization of a mean curvature type energy called the Helfrich bending energy.In this formalism,the equilibrium shape of a cell vesicle may present itself in a rich variety of geometric and topological characteristics.We first show that there is an obstruction,arising from the spontaneous curvature,to the existence of a minimizer of the Helfrich energy over the set of embedded ring tori.We then propose a scale-invariant anisotropic bending energy,which extends the Canham energy,and show that it possesses a unique toroidal energy minimizer,up to rescaling,in all parameter regime.Furthermore,we establish some genus-dependent topological lower and upper bounds,which are known to be lacking with the Helfrich energy,for the proposed energy.We also present the shape equation in our context,which extends the Helfrich shape equation.The second application arises from astrophysics in the search for a mechanism for matter accretion in the early universe in the context of cosmic strings.In this formalism,gravitation may simply be stored over a two-surface so that the Einstein tensor is given in terms of the Gauss curvature of the surface which relates itself directly to the Hamiltonian energy density of the matter sector.This setting provides a lucid exhibition of the interplay of the underlying geometry,matter energy,and topological characterization of the system.In both areas of applications,we encounter highly challenging nonlinear partial differential equation problems.We demonstrate that studies on these equations help us to gain understanding of the theoretical physics problems considered.展开更多
基金This work was supported by the Radiology Research Fund for Alzheimer’s Disease at Stanford University(to AST).
文摘Alzheimer’s disease is a progressive and fatal neurodegenerative disorder that starts many years before the onset of cognitive symptoms.Identifying novel biomarkers for Alzheimer’s disease has the potential for patient risk stratification,early diagnosis,and disease monitoring in response to therapy.A novel class of biomarkers is extracellular vesicles given their sensitivity and specificity to specific diseases.In addition,extracellular vesicles can be used as novel biological therapeutics given their ability to efficiently and functionally deliver therapeutic cargo.This is critical given the huge unmet need for novel treatment strategies for Alzheimer’s disease.This review summarizes and discusses the most recent findings in this field.
文摘The most prevalent form of dementia in the elderly is Alzheimer's disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42(Aβ42),a small hydrophobic peptide.Unfortunately,attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease.It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach.The accumulation of Aβ42 seems to affect various aspects of physiological cell functions.In this review,we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction,with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release.We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer's disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease.Although the precise mechanisms that trigger synaptic dysfunction are still under investigation,the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.
基金supported by the National Natural Science Foundation of China,No.82074533(to LZ).
文摘Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.
文摘Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.
基金supported by the Research Project of the Shanghai Health Commission,No.2020YJZX0111(to CZ)the National Natural Science Foundation of China,Nos.82021002(to CZ),82272039(to CZ),82171252(to FL)+1 种基金a grant from the National Health Commission of People’s Republic of China(PRC),No.Pro20211231084249000238(to JW)Medical Innovation Research Project of Shanghai Science and Technology Commission,No.21Y11903300(to JG).
文摘Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.
文摘INTRODUCTION Our previous study has proved that Kupffer cellsmay have an inhibitory effect on the process ofhepatocarcinogenesis,however,their inhibitorymechanism needs exploring deeply.We performed acomparative study on the expression of PCNA,Bax,P53 and apoptosis of liver cancer cells usingimmunohistochemical technology and terminaldeoxynucleotidyl transferase (TdT)-mediateddUTP-digoxigenin nick end labeling(TUNEL)
基金supported by the National Key Research and Development Program (grant no. 2021YFA1101301)the National Natural Science Foundation of China (grant no. 82225027, 82271419, 81820108013, 62127810, 81901902)+1 种基金Shanghai Rising-Star Program (grant no. 22QA1408200)the Fundamental Research Funds for the Central Universities(no. 22120220555, no. 22120230292, no. 22120230138)
文摘Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241(EVs-AM1241)to protect against neurodegenerative progression and neuronal function in AD model mice.According to the results,EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241.The Morris water maze(MWM)and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved.In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning.Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloidβ(Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241.Moreover,EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton,indicating that they enhanced neuronal regeneration.RNA sequencing revealed that EVs-AM1241 facilitated Aβphagocytosis,promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway.Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in modelmice,indicating that they are very promising particles for treating AD.
基金supported by funding from the Creutzfeldt-Jakob Disease FoundationInc.(USA)+4 种基金the Alzheimer Forschung Initiative (AFI e.V.,Germany)the Werner-Otto-Stiftung (Hamburg,Germany)(all to HCA)the China Scholarship Council (to FS)European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie Grant Agreement N°101030402 (to AMA)Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Center (CRC) 877"Proteolysis as a regulatory event in pathophysiology"(to MG)。
文摘In the last decades,the role of the prion protein(PrP) in neurodegenerative diseases has been intensively investigated,initially in prion diseases of humans(e.g., Creutzfeldt-J akob disease) and animals(e.g.,scrapie in sheep,chronic wasting disease in deer and elk,or "mad cow disease" in cattle).Templated misfolding of physiological cellular prion protein(PrPC) into an aggregation-prone isoform(termed PrP "Scrapie"(PrPSc)),self-re plication and spreading of the latter inside the brain and to peripheral tissues,and the associated formation of infectious proteopathic seeds(termed "prions")are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies.Late r,key roles of the correctly folded PrPCwere identified in more common human brain diseases(such as Alzheimer s disease or Parkinson’s disease) associated with the misfolding and/or accumulation of other proteins(such as amyloid-β,tau or α-synuclein,respectively).PrPChas also been linked with n euro protective and regenerative functions,for instance in hypoxic/ischemic conditions such as stroke.However,despite a mixed "bouquet" of suggested functions,our understanding of pathological and,especially,physiological roles played by PrPCin the brain and beyond is ce rtainly incomplete.Interactions with various other proteins at the cell surfa ce or within intracellular compartments may account for the functional diversity linked with PrPC.Moreover,conserved endogenous proteolytic processing of PrPCgenerates seve ral defined PrPCfragments,possibly holding intrinsic functions in physiological and pathological conditions,thus making the "true and complete biology" of this protein more complicated to be elucidated.Here,we focus on one of those released PrPCfragments,namely shed PrP(sPrP),generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surfa ce.Similar to other soluble PrP fragments(such as the N1 fragment representing PrP’s released N-terminal tail upon the major α-cleavage event)or expe rimentally employed recombinant PrP,sPrP is being suggested to act n euro protective in Alzheimer’s disease and other protein misfolding diseases.Seve ral lines of evidence on extracellular PrPC(fragments) suggest that induction of PrPCrelease co uld be a future therapeutic option in various brain disorders.Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM 10,based on ligands binding to cell surface PrPC,may further set the stage for research into this direction.
基金Supported by the National Key R&D Program of China(No.2018YFC1406406)the Science and Technology Program of Yantai(Nos.2018SFBF084,2019ZDCX018)。
文摘Fish embryos are widely used as models in toxicology,drug development,and human disease research because of their high sensitivity,observability,and operability,providing the basis for an in-depth understanding of the embryogenesis.Increasing studies have indicated that birth defects are hereditary.In this study,we used Oryzias melastigma as a model to conduct a study of 185-day embryogenesis and observed self-induced non-pathological abnormal embryogenesis.O.melastigma experienced pre-puberty stage,adolescence stage,and senescence stage,and individuals produced up to 102 eggs per day.However,the fecundity was markedly reduced during the senescent stage.During the active egg and blastodisc stages,pseudo-fertilization and pseudo-blastocysts were observed.During cleavage at the 4-to 32-cell stages,we observed blastomeres separation or dislocation.Excessively separated blastomeres formed double blastoderms,eventually resulting in conjoined twins.During the blastula stage,we observed abnormally increased cell volume,narrowed and elongated blastocysts,and abnormally coated blastoderms.At the organogenesis stage,we observed abnormal numbers of Kupff er’s vesicles and conjoined twins.Abnormality in the location and number of oil droplets were observed in various development stages.Abnormal development was more commonly observed in fertilized eggs produced by broodstock in pre-puberty or senescence stages,which is probably related to the age of fish and the egg quality.This study can provide the materials for comparative analysis in toxicological and molecular studies of O.melastigma,and may provide evidence for other economic fish that produce sticky eggs.
文摘Zinner syndrome is a rare congenital malformation related to an abnormality in the development of the Wolffian duct, the clinical picture of which consists of a triad of unilateral renal agenesis, ipsilateral seminal vesicle cyst, and obstruction of the ejaculatory duct. Chronic perineoscrotal pain may be an indication of the diagnosis of Z<span style="white-space:nowrap;">ï</span>nner syndrome to some extent. We report the observation of a 23-year-old patient, married and father of one child, who presented with chronic perineo-scrotal pain revealing on morphological assessment (ultrasound, uroscanner, prostatic MRI) a cystic formation of the seminal vesicle, left renal agenesis with an empty left renal compartment. Given the patient’s refusal of any surgical procedure, treatment consisted of echo-guided puncture of the seminal vesicle cyst bringing back 30 cc of a seroviscous liquid whose analysis revealed spermatozoa, without atypical cells, compatible with a cyst. The clinical evolution was marked by a progressive remission of the scrotal pain with a delay of several months.
基金This work was supported by the National Natural Science Foundation of China ((Nos. 21420102007, 21234004, 21574056, 91527302), the Chang Jiang Scholars Program of China, and Project 2016014 Sup- ported by Graduate Innovation Fund of Jilin University.
文摘Redox responsive vesicles were constructed based on guest interaction between fl-cyclodextrin and a ferrocene self-assembly of a supra-amphiphile built by the host- derivative. The structure and destruction-reconstruction reversibility of the "smart" vesicles were clearly characterized by electron microscopy and dynamic light scattering. Notably, these vesicles were proved to be capable of controlled release function and bringing protease resistance to the enzyme, showing great biocompatibility and promising applications.
基金This work was supported by the National Key Research and Development Program of China(2016YFC1306603 to Q.Y.)the National Natural Science Foundation of China(NSFC+1 种基金31930048 and 31671060 to Q.Y.,and 61972320 to B.C.)the Projects of International Cooperation and Exchange under NSFC(81720108016,Q.Y.).
文摘Background:Blood-based test for predicting disease progression and early diagnosis of Parkinson’s disease(PD)is an unmet need in the clinic.The profiles of microRNAs(miRNAs)are regarded as potential diagnostic biomarkers for human diseases,whereas miRNAs in the periphery are susceptible to the influence of various components.MiRNAs enriched in serum extracellular vesicles(EVs)have demonstrated disease-specific advantages in diagnosis due to their high abundance,stability and resistance to degradation.This study was aimed to screen differentially expressed EV-derived miRNAs between healthy controls and PD patients to aid in diagnosis of PD.Methods:A total of 31 healthy controls and 72 patients with a diagnosis of PD at different Hoehn and Yahr stages in Tangdu Hospital were included.In total,185 differentially expressed miRNAs were obtained through RNA sequencing of serum EVs as well as edgeR and t-test analyses.Subsequently,the weighted gene co-expression network analysis(WGCNA)was utilized to identify the commonly expressed miRNAs in all stages of PD by constructing connections between modules,and specifically expressed miRNAs in each stage of PD by functional enrichment analysis.After aligning these miRNAs with PD-related miRNAs in Human miRNA Disease Database,the screened miRNAs were further validated by receiver operating characteristic(ROC)curves and quantitative real-time polymerase chain reaction(qRT-PCR)using peripheral blood EVs from 40 more participants.Results:WGCNA showed that 4 miRNAs were commonly associated with all stages of PD and 13 miRNAs were specifically associated with different stages of PD.Of the 17 obtained miRNAs,7 were validated by ROC curve analysis and 7 were verified in 40 more participants by qRT-PCR.Six miRNAs were verified by both methods,which included 2 miRNAs that were commonly expressed in all stages of PD and 4 miRNAs that were specifically expressed in different stages of PD.Conclusions:The 6 serum EV-derived miRNAs,hsa-miR-374a-5p,hsa-miR-374b-5p,hsa-miR-199a-3p,hsa-miR-28-5p,hsa-miR-22-5p and hsa-miR-151a-5p,may potentially be used as biomarkers for PD progression and for early diagnosis of PD in populations.
基金This work has been developed and supported through the LABEX(excellence laboratory,program investment for the future)DISTALZ(Development of lnnovative Strategies for a Transdisciplinary approach to ALZheimers disease)and by Fondation Alzheimer.A.Be and A.Bo were granted from DISTALZ.
文摘Background:We recently demonstrated an endolysosomal accumulation of theβ-secretase-derived APP C-terminal fragment(CTF)C99 in brains of Alzheimer disease(AD)mouse models.Moreover,we showed that the treatment with theγ-secretase inhibitor(D6)led to further increased endolysosomal APP-CTF levels,but also revealed extracellular APP-CTF-associated immunostaining.We here hypothesized that this latter staining could reflect extracellular vesicle(EV)-associated APP-CTFs and aimed to characterize theseγ-secretase inhibitor-induced APPCTFs.Methods:EVs were purified from cell media or mouse brains from vehicle-or D6-treated C99 or APPswedish expressing cells/mice and analyzed for APP-CTFs by immunoblot.Combined pharmacological,immunological and genetic approaches(presenilin invalidation and C99 dimerization mutants(GXXXG))were used to characterize vesicle-containing APP-CTFs.Subcellular APP-CTF localization was determined by immunocytochemistry.Results:Purified EVs from both AD cell or mouse models were enriched in APP-CTFs as compared to EVs from control cells/brains.Surprisingly,EVs from D6-treated cells not only displayed increased C99 and C99-derived C83 levels but also higher molecular weight(HMW)APP-CTF-immunoreactivities that were hardly detectable in whole cell extracts.Accordingly,the intracellular levels of HMW APP-CTFs were amplified by the exosomal inhibitor GW4869.By combined pharmacological,immunological and genetic approaches,we established that these HMW APP-CTFs correspond to oligomeric APP-CTFs composed of C99 and/or C83.Immunocytochemical analysis showed that monomers were localized mainly to the trans-Golgi network,whereas oligomers were confined to endosomes and lysosomes,thus providing an anatomical support for the selective recovery of HMW APP-CTFs in EVs.The D6-induced APP-CTF oligomerization and subcellular mislocalization was indeed due toγ-secretase blockade,since it similarly occurred in presenilin-deficient fibroblasts.Further,our data proposed that besides favoring APP-CTF oligomerization by preventing C99 proteolysis,γ-secretase inhibiton also led to a defective SorLA-mediated retrograde transport of HMW APP-CTFs from endosomal compartments to the TGN.Conclusions:This is the first study to demonstrate the presence of oligomeric APP-CTFs in AD mouse models,the levels of which are selectively enriched in endolysosomal compartments including exosomes and amplified byγ-secretase inhibition.Future studies should evaluate the putative contribution of these exosome-associated APP-CTFs in AD onset,progression and spreading.
基金Supported by National Natural Science Foundation of China(Grant No.11471100)。
文摘In this survey article,we present two applications of surface curvatures in theoretical physics.The first application arises from biophysics in the study of the shape of cell vesicles involving the minimization of a mean curvature type energy called the Helfrich bending energy.In this formalism,the equilibrium shape of a cell vesicle may present itself in a rich variety of geometric and topological characteristics.We first show that there is an obstruction,arising from the spontaneous curvature,to the existence of a minimizer of the Helfrich energy over the set of embedded ring tori.We then propose a scale-invariant anisotropic bending energy,which extends the Canham energy,and show that it possesses a unique toroidal energy minimizer,up to rescaling,in all parameter regime.Furthermore,we establish some genus-dependent topological lower and upper bounds,which are known to be lacking with the Helfrich energy,for the proposed energy.We also present the shape equation in our context,which extends the Helfrich shape equation.The second application arises from astrophysics in the search for a mechanism for matter accretion in the early universe in the context of cosmic strings.In this formalism,gravitation may simply be stored over a two-surface so that the Einstein tensor is given in terms of the Gauss curvature of the surface which relates itself directly to the Hamiltonian energy density of the matter sector.This setting provides a lucid exhibition of the interplay of the underlying geometry,matter energy,and topological characterization of the system.In both areas of applications,we encounter highly challenging nonlinear partial differential equation problems.We demonstrate that studies on these equations help us to gain understanding of the theoretical physics problems considered.