Recent studies have shown that microglia/macrophages and astrocytes can mediate synaptic phagocytosis through the MER proto-oncokinase in developmental or stroke models,but it is unclear whether the same mechanism is ...Recent studies have shown that microglia/macrophages and astrocytes can mediate synaptic phagocytosis through the MER proto-oncokinase in developmental or stroke models,but it is unclear whether the same mechanism is also active in traumatic brain injury.In this study,we established a mouse model of traumatic brain injury and found that both microglia/macrophages and astrocytes phagocytosed synapses and expression of the MER proto-oncokinase increased 14 days after injury.Specific knockout of MER in microglia/macrophages or astrocytes markedly reduced injury volume and greatly improved neurobehavioral function.In addition,in both microglia/macrophages-specific and astrocytes-specific MER knock-out mice,the number of microglia/macrophage and astrocyte phagocytosing synapses was markedly decreased,and the total number of dendritic spines was increased.Our study suggested that MER proto-oncokinase expression in microglia/macrophages and astrocytes may play an important role in synaptic phagocytosis,and inhibiting this process could be a new strategy for treating traumatic brain injury.展开更多
The fuorescence-based in vivo flow cytometry(IVFC)is an emerging tool to monitor eirculating cells in vivo.As a noninvasive and real-timne diagnostic technology,the fluorescence based IVFC allows long-term monitoring ...The fuorescence-based in vivo flow cytometry(IVFC)is an emerging tool to monitor eirculating cells in vivo.As a noninvasive and real-timne diagnostic technology,the fluorescence based IVFC allows long-term monitoring of circulating cells without changing their native biological environment.It has been applied for various biological applications(eg,monitoring circulating tumor cells).In this work,we will review our recent works on fluorescence-based IVFC.The operation principle and typical biological applications will be introduced.In addition,the recent advances in IVFC flow cytometry based on photoacoustic effects and other label free detection methods such as imaging based methods,difuse-light methods,hybrid multimodality methods and multispectral methods are also summarized.展开更多
Alzheimers disease(AD)is a chronic neurodegenerative disease.The symptoms include memoryand spatial learning dificulties,language disorders,and loss of motivation,which get worse overtime,eventually ending in death.No...Alzheimers disease(AD)is a chronic neurodegenerative disease.The symptoms include memoryand spatial learning dificulties,language disorders,and loss of motivation,which get worse overtime,eventually ending in death.No ffective treatments are available for AD,currently.Currenttreatments only attenuate symptoms temporarily and are associated with severe side ffects.Nearinfra-red(NIR)light has been studied for a long time.We investigated the effect of NIR on ADusing a transgenic mouse model,which was obtained by co-injecting two vectors carrying ADmutations in amyloid precursor protein(APP)and presenilin-i(PSEN1)into C57BL/6J mice.The irradiation equipment consisted of an accommodating box and an LED array.The wave-length of NIR light emitted from LED was between 1040 nm and 1090 nm.The power densitydelivered at the level of the mice was approximately 15 mW/cm^(2),Firstly,we treated the micewith NIR for 40 days,Then,the irradiation was suspended for 28 days.Finally,another 15 daystreatment was brought to mice.We conducted Morris water maze and immunofluorescenceanalysis to evaluate the effects of treatment.Immunofuorescence analysis was based on mea-suring the quantity of plaques in mouse brain slices,Our results show that NIR light improvesmemory and spatial learning ability and reduces plaques moderately.NIR light represents apotential treatment for AD.展开更多
Blood-brain barrier(BBB)disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke.Reducing this disruption has therapeutic potential.Transcranial focused ultrasound stimulation ...Blood-brain barrier(BBB)disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke.Reducing this disruption has therapeutic potential.Transcranial focused ultrasound stimulation has shown neuromodulatory and neuroprotective effects in various brain diseases including ischemic stroke.Ultrasound stimulation can reduce inflammation and promote angiogenesis and neural circuit remodeling.However,its effect on the BBB in the acute phase of ischemic stroke is unknown.In this study of mice subjected to middle cerebral artery occlusion for 90 minutes,low-intensity low-frequency(0.5 MHz)transcranial focused ultrasound stimulation was applied 2,4,and 8 hours after occlusion.Ultrasound stimulation reduced edema volume,improved neurobehavioral outcomes,improved BBB integrity(enhanced tight junction protein ZO-1 expression and reduced IgG leakage),and reduced secretion of the inflammatory factors tumor necrosis factor-αand activation of matrix metalloproteinase-9 in the ischemic brain.Our results show that low-intensity ultrasound stimulation attenuated BBB disruption and edema formation,which suggests it may have therapeutic use in ischemic brain disease as a protector of BBB integrity.展开更多
Catalysis-based chemodynamic therapy(CDT)is an emerging cancer treatment strategy which uses a Fenton-like reaction to kill tumor cells by catalyzing endogenous hydrogen peroxide(H_(2)O_(2))into a toxic hydroxyl radic...Catalysis-based chemodynamic therapy(CDT)is an emerging cancer treatment strategy which uses a Fenton-like reaction to kill tumor cells by catalyzing endogenous hydrogen peroxide(H_(2)O_(2))into a toxic hydroxyl radical(·OH).The performance of CDT is greatly dependent on PDT agent.Herein,mitochondria-targeting Pt nanoclusters were synthesized using cytochrome c aptamer(CytcApt)as template.The obtained CytcApt-PtNCs can produce.OH by H_(2)O_(2)under the acidic conditions.Moreover,CytcApt-PtNCs could kill 4T1 tumor cells in a pH-dependent manner,but had no side effect on normal 293T cells.Therefore,CytcApt-PtNCs possess excellent therapeutic effect and good biosafety,indicating their great potential for CDT.展开更多
Recent studies in oncology have addressed the importance of detecting circulating tumor cell clusters because circulating tumor cell clusters might survive and metastasize more easily than single circulating tumor cel...Recent studies in oncology have addressed the importance of detecting circulating tumor cell clusters because circulating tumor cell clusters might survive and metastasize more easily than single circulating tumor cells.Signals with larger peak widths detected by in vivo flow cytometer(IVFC)have been used to identify cell clusters in previous studies.However,the accuracy of this criterion might be greatly degraded by variance in blood°ow and the rolling behaviors of circulating tumor cells.Here,we propose a criterion and algorithm to distinguish cell clusters from single cells.In this work,we first used area-based and volume-based models for single°uorescent cells.Simulating each model,we analyzed the corresponding morphology of IVFC signals from cell clusters.According to the Rayleigh criterion,the valley between two adjacent peak signals from two distinguishable cells should be lower than 73.5%of the peak values.A novel signal processing algorithm for IVFC was developed based on this criterion.The results showed that cell clusters can be reliably identied using our proposed algorithm.Intravital imaging was also performed to further support our algorithm.With enhanced accuracy,IVFC is a powerful tool to study circulating cell clusters.展开更多
In biomedical research fields,the in vio Aow cytometry(IVFC)is a widely used technology which is able to monitor target cells dynamically in living animals.Although the setup of IVFC system has been well established,b...In biomedical research fields,the in vio Aow cytometry(IVFC)is a widely used technology which is able to monitor target cells dynamically in living animals.Although the setup of IVFC system has been well established,baseline drift is still a challenge in the process of quantifying circulating cells.Previous methods,i.e.,the dynamic peak picking method,counted cells by setting a static threshold without considering the baseline drift,leading to an inaccurate cell quantification.Here,we developed a method of cell counting for IVFC data with baseline drift by interpolation fitting,automatic segmentation and wavelet-based denoising.We demonstrated its performance for IVFC signals with three types of representative baseline drift.Compared with non-baseline correction methods,this method showed a higher sensitivity and specificity,as well as a better result in the Pearson's correlation coefficient and the mean-squared error(MSE).展开更多
T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an init...T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an initial signal of T-cell activation,has been found to occur before IS for-mation.The mechanism for triggering the calcium signaling and relationship bet ween calciumrelease and IS format ion remains unclear.Herein,using live-cell imaging,we found that int ercellularadhesion molecule 1(ICAM-1),an essential mdlecule for IS formation,accumulated and then wasdepleted at the center of the synapse before complete IS formation.During the proces of ICAM1depletion,calcium was released.if ICAM-1 failed to be depleted from the center of the synapse,thesustained calcium signaling could not be induced.Moreover,depletion of ICAM-1 in ISs preferen-tially ccurred with the contact of antigen-specific T-cels and dendritic clls(DCs).Blocking thebinding ofICA M-1 and lymphocy te finction-associated antigen 1(LFA-1),ICAM-1 failed to depleteat the center of the synapse,and calcium release in T-clls decreased.In studying the mechanism ofhow the depletion ofiCA M1 could influence calcium release in T-clls,we found that the movementof ICAM-1 was associat ed with the localization of LFA-1 in the IS,which afected the localization ofcalcium microdomains,ORAIl and mitochondria in IS.Therefore,the depletion of ICAM-1 in the center of the synapse is an important factor for an initial sust ained calcium release in T-cells.展开更多
Dear Editor,Nanotechnology-based therapeutic strategies have been proven effective in diseases including cancer,infection,inflammation,etc.1 However,the application of nanotechnology is greatly restricted in the treat...Dear Editor,Nanotechnology-based therapeutic strategies have been proven effective in diseases including cancer,infection,inflammation,etc.1 However,the application of nanotechnology is greatly restricted in the treatment of central nervous system(CNS)disorders due to physiological CNS barriers.For example,the blood-brain barrier(BBB)can be the“Maginot line”for pharmacologically active molecules,blocking them out of the CNS.展开更多
Stroke is the second most common cause of death in the world especially in the ageing population.1 Thrombolysis and intravascular embolectomy are the main treatment and populated rapidly.23 However,the benefi-ciary is...Stroke is the second most common cause of death in the world especially in the ageing population.1 Thrombolysis and intravascular embolectomy are the main treatment and populated rapidly.23 However,the benefi-ciary is still limited because the mechanistic studies are behind.The basic research on stroke is improved because of new devices,novel techniques and the development of other disciplines.4 The update of a broad range of topics related to stroke is a widely appreciated feature.In order to improve the understanding of cellular and molecular mechanisms of stroke,the 2nd Summit of Chinese Basic Science Research on Stroke 2018 has been held in Beijing,China.展开更多
Central nervous system(CNS)injuries,including stroke,traumatic brain injury,and spinal cord injury,are essential causes of death and long-term disability and are difficult to cure,mainly due to the limited neuron rege...Central nervous system(CNS)injuries,including stroke,traumatic brain injury,and spinal cord injury,are essential causes of death and long-term disability and are difficult to cure,mainly due to the limited neuron regeneration and the glial scar formation.Herein,we apply extracellular vesicles(EVs)secreted by M2 microglia to improve the differentiation of neural stem cells(NSCs)at the injured site,and simultaneously modify them with the injured vascular targeting peptide(DA7R)and the stem cell recruiting factor(SDF-1)on their surface via copper-free click chemistry to recruit NSCs,inducing their neuronal differentiation,and serving as the nanocarriers at the injured site(Dual-EV).Results prove that the Dual-EV could target human umbilical vascular endothelial cells(HUVECs),recruit NSCs,and promote the neuronal differentiation of NSCs in vitro.Furthermore,10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis,and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs,miR30b-3p,miR-222-3p,miR-129-5p,and miR-155-5p may exert effect of inducing NSC to differentiate into neurons.In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice,potentiate NSCs recruitment,and increase neurogenesis.This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells,and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health.展开更多
Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially s...Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially successful in regressing prostate tumors, the disease ultimately comes back as castration-resistant prostate cancer (CRPC) or at the late stage as neuroendocrine prostate cancer (NEPC). CRPC remains largely dependent on hyperactive AR signaling in the milieu of low androgen, while NEPC is negative of AR expression but positive of many AR-repressed genes. Recent technological advances in genome-wide analysis of transcription factor binding sites have revealed an unprecedented set of AR target genes. In addition to its well-known function in activating gene expression, AR is increasingly known to also act as a transcriptional repressor. Here, we review the molecular mechanisms by which AR represses gene expression. We also summarize AR-repressed genes that are aberrantly upregulated in CRPC and NEPC and represent promising targets for therapeutic intervention.展开更多
Photodynamic therapy(PDT),which utilizes light excite photosensitizers(PSs)to generate reactive oxygen species(ROS)and consequently ablate cancer cells or diseased tissue,has attracted a great deal of attention in the...Photodynamic therapy(PDT),which utilizes light excite photosensitizers(PSs)to generate reactive oxygen species(ROS)and consequently ablate cancer cells or diseased tissue,has attracted a great deal of attention in the last decades due to its unique advantages.However,the advancement of PDT is restricted by the inherent characteristics of PS and tumor microenvironment(TME).It is urgent to explore high-performance PSs with TME regulation capability and subsequently improve the therapeutic outcomes.Herein,we reported a newly engineered PS of polymer encapsulated carbonized hemin nanoparticles(P-CHNPs)via a facile synthesis procedure for boosting photodynamic anticancer therapy.Solvothermal treatment of hemin enabled the synthesized P-CHNPs to enhance oxidative stress in TME,which could be further amplified under light irradiation.Excellent in vitro and in vivo PDT effects were achieved due to the improved ROS(hydroxyl radicals and singlet oxygen)generation efficiency,hypoxia relief,and glutathione depletion.Moreover,the superior in vitro and in vivo biocompatibility and boosted PDT effect make the P-CHNPs a potential therapeutic agent for future translational research.展开更多
Circulating tumor cells(CTCs)is an established biomarker of cancer metastasis.The circulation dynamics of CTCs are important for understanding the mechanisms underlying tumor cell dissemination.Although studies have r...Circulating tumor cells(CTCs)is an established biomarker of cancer metastasis.The circulation dynamics of CTCs are important for understanding the mechanisms underlying tumor cell dissemination.Although studies have revealed that the circadian rhythm may disrupt the growth of tumors,it is generally unclear whether the circadian rhythm controls the release of CTCs.In clinical examinations,the current in vitro methods for detecting CTCs in blood samples are based on a fundamental assumption that CTC counts in the peripheral blood do not change significantly over time,which is being challenged by recent studies.Since it is not practical to draw blood from patients repeatedly,a feasible strategy to investigate the circadian rhythm of CTCs is to monitor them by in vivo detection methods.Fluoresce nee in vivo flow cytometry(IVFC)is a powerful optical technique that is able to detect fluoresce nt circulating cells directly in living animals in a noninvasive manner over a long period of time.In this study,we applied fluorescence IVFC to monitor CTCs noninvasively in an orthotopic mouse model of human prostate cancer.We observed that CTCs exhibited stochastic bursts over cancer progression.The probability of the bursting activity was higher at early stages than at late stages.We longitudinally monitored CTCs over a 24-h period,and our results revealed striking daily oscillations in CTC counts that peaked at the onset of the night(active phase for rodents),suggesting that the release of CTCs might be regulated by the circadian rhythm.展开更多
Dear Editor,We thank Niedre et al.for their correspondence regarding our recent paper1.They proposed a point that the temporal distribution of circulating tumor cells(CTCs)monitored by diffuse in vivo flow cytometry i...Dear Editor,We thank Niedre et al.for their correspondence regarding our recent paper1.They proposed a point that the temporal distribution of circulating tumor cells(CTCs)monitored by diffuse in vivo flow cytometry in a multiple myeloma mouse model in their previous work2 might be different from our results.Niedre et al.claimed that CTC detection statistics deviated from Poisson but did not found circadian variations in CTC numbers in a multiple myeloma mouse model.They also cite another literature by Juratli.et al.3,in which the authors reported that CTC numbers did not always correlate with tumor size during cancer progression.However,by establishing an orthotopic mouse model of prostate cancer and utilizing the technology in vivo flow cytometry(IVFC),we found CTCs exhibited bursting activity and daily oscillation in an orthotopic model of prostate cancer.展开更多
Photobiomodulation,by utilizing low-power light in the visible and near-infrared spectra to trigger biological responses in cells and tissues,has been considered as a possible therapeutic strategy for Alzheimer’s dis...Photobiomodulation,by utilizing low-power light in the visible and near-infrared spectra to trigger biological responses in cells and tissues,has been considered as a possible therapeutic strategy for Alzheimer’s disease(AD),while its specific mechanisms have remained elusive.Here,we demonstrate that cognitive and memory impairment in an AD mouse model can be ameliorated by 1070-nm light via reducing cerebralβ-amyloid(Aβ)burden,the hallmark of AD.The glial cells,including microglia and astrocytes,play important roles in Aβclearance.Our results show that 1070-nm light pulsed at 10 Hz triggers microglia rather than astrocyte responses in AD mice.The 1070-nm lightinduced microglia responses with alteration in morphology and increased colocalization with Aβare sufficient to reduce Aβload in AD mice.Moreover,1070-nm light pulsed at 10 Hz can reduce perivascular microglia and promote angiogenesis to further enhance Aβclearance.Our study confirms the important roles of microglia and cerebral vessels in the use of 1070-nm light for the treatment of AD mice and provides a framework for developing a novel therapeutic approach for AD.展开更多
Stroke is the second leading cause of mortality and morbidity worldwide.Early intervention is of great importance in reducing disease burden.Since the conventional risk factors cannot fully account for the pathogenesi...Stroke is the second leading cause of mortality and morbidity worldwide.Early intervention is of great importance in reducing disease burden.Since the conventional risk factors cannot fully account for the pathogenesis of stroke,it is extremely important to detect useful biomarkers of the vascular disorder for appropriate intervention.Arterial stiffness,a newly recognised reliable feature of arterial structure and function,is demonstrated to be associated with stroke onset and serve as an independent predictor of stroke incidence and poststroke functional outcomes.In this review article,different measurements of arterial stiffness,especially pressure wave velocity,were discussed.We explained the association between arterial stiffness and stroke occurrence by discussing the secondary haemodynamic changes.We reviewed clinical data that support the prediction role of arterial stiffness on stroke.Despite the lack of long-term randomised double-blind controlled therapeutic trials,it is high potential to reduce stroke prevalence through a significant reduction of arterial stiffness(which is called de-stiffening therapy).Pharmacological interventions or lifestyle modification that can influence blood pressure,arterial function or structure in either the short or long term are promising de-stiffening therapies.Here,we summarised different de-stiffening strategies including antihypertension drugs,antihyperlipidaemic agents,chemicals that target arterial remodelling and exercise training.Large and well-designed clinical trials on de-stiffening strategy are needed to testify the prevention effect for stroke.Novel techniques such as modern microscopic imaging and reliable animal models would facilitate the mechanistic analyses in pathophysiology,pharmacology and therapeutics.展开更多
Platelets buoy up cancer metastasis via arresting cancer cells, enhancing their adhesion, and facilitating their extravasation through the vasculature. When deprived of intracellular and granular contents, platelet de...Platelets buoy up cancer metastasis via arresting cancer cells, enhancing their adhesion, and facilitating their extravasation through the vasculature. When deprived of intracellular and granular contents, platelet decoys could prevent metastatic tumor formation. Inspired by these, we developed nanoplatesomes by fusing platelet membranes with lipid membranes(P-Lipo) to restrain metastatic tumor formation more efficiently. It was shown nanoplateletsomes bound with circulating tumor cells(CTC)efficiently, interfered with CTC arrest by vessel endothelial cells, CTC extravasation through endothelial layers, and epithelial-mesenchymal transition of tumor cells as nanodecoys. More importantly, in the mouse breast tumor metastasis model, nanoplateletsomes could decrease CTC survival in the blood and counteract metastatic tumor growth efficiently by inhibiting the inflammation and suppressing CTC escape. Therefore, nanoplatelesomes might usher in a new avenue to suppress lung metastasis.展开更多
Diabetes is usually associated with cerebrovascular disease,especially stroke.In practice,fasudil is widely accepted to be applied for the treatment of vascular disease.This article demonstrates the study concentratin...Diabetes is usually associated with cerebrovascular disease,especially stroke.In practice,fasudil is widely accepted to be applied for the treatment of vascular disease.This article demonstrates the study concentrating on the effects of fasudil pretreatment on the prognosis of diabetic stroke.250—300 g SpragueDawley rats were randomly divided into three groups,non-diabetic stroke group,diabetic stroke group,and fasudil pretreatment group.The rats of diabetes group were treated with intraperitoneal injection of streptozotocin(60 mg/kg),in the meantime the same dose of citrate buffer was injected into those of the control group.The rats of the fasudil group received daily fasudil intraperitoneal injection at 10 mg/kg for three consecutive weeks.After four weeks,all the rats of the experimental group were treated with middle cerebral artery occlusion for 90 min.After sacrifice,the fresh brain samples were collected for following experiments,including infarct volume,edema volume,blood-brain barrier(BBB),which were detected by immunohistochemistry.Inflammatory factors were examined by real-time polymerase chain reaction(RT-PCR)using tissue Ribonucleic Acid(RNA).The concentration of blood glucose is 15 mmol/L or more,which proved that the diabetes model was a success.Fasudil pretreatment decreases the percentage of stroke mortality of diabetes from 43.75%to 31.25%,while the infarction volume decreases from 52.95%±12.7%to 45.97%±6.7%.Gap formation of tight junction and Immunoglobulin G(Ig G)leakage were reduced(P<0.05),and the expression of inflammatory factors decreases(P<0.05)in fasudil pretreatment after diabetic stroke.Diabetes aggravates the mortality of cerebral ischemic rats.Prolonged fasudil pretreatment can reduce mortality of diabetic stroke,decrease cerebral infarction volume and undermine inflammatory factors expression,and protect the BBB.展开更多
MicroRNA-126 was involved in angiogenesis during physiological and pathological process. It was mainly expressed in endothelial cells, and defined as a pivotal biological molecule associated with vascular disease. Inc...MicroRNA-126 was involved in angiogenesis during physiological and pathological process. It was mainly expressed in endothelial cells, and defined as a pivotal biological molecule associated with vascular disease. Increased microRNA-126 in endothelial cells promotes angiogenesis in ischemic stroke, repairs impaired endothelial cells in atherosclerosis, and attenuates vascular dysfunction in diabetics. By contrast, microRNA-126 transferred from endothelial cell to smooth muscle cells could lead to proliferation that induced intimal hyperplasia. Additionally, microRNA-126 could be a tumor suppressor or an oncogene, which was depended on the cancer type. In this review, we summarized the function of microRNA-126 in ischemic stroke, atherosclerosis, diabetics, tumor, and discussed the underlying mechanisms.展开更多
基金supported by the National Key R&D Program of China,No.2019YFA0112000(to YHT)the National Natural Science Foundation of China,Nos.82071284(to YHT),81974179(to ZJZ)+4 种基金Shanghai Rising-Star Program,No.21QA1405200(to YHT)the Scientific Research and Innovation Program of Shanghai Education Commission,No.2019-01-07-00-02-E00064(to GYY)Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission,No.20JC1411900(to GYY)the Notional Research Foundation of Korea,Nos.2020M3E5D9079912(to WSC),2021R1A2C3005704(to WSC),2022M3E5E8081188(to WSC)the Korea Health Technology R&D Project,No.HU20C0290(to WSC)。
文摘Recent studies have shown that microglia/macrophages and astrocytes can mediate synaptic phagocytosis through the MER proto-oncokinase in developmental or stroke models,but it is unclear whether the same mechanism is also active in traumatic brain injury.In this study,we established a mouse model of traumatic brain injury and found that both microglia/macrophages and astrocytes phagocytosed synapses and expression of the MER proto-oncokinase increased 14 days after injury.Specific knockout of MER in microglia/macrophages or astrocytes markedly reduced injury volume and greatly improved neurobehavioral function.In addition,in both microglia/macrophages-specific and astrocytes-specific MER knock-out mice,the number of microglia/macrophage and astrocyte phagocytosing synapses was markedly decreased,and the total number of dendritic spines was increased.Our study suggested that MER proto-oncokinase expression in microglia/macrophages and astrocytes may play an important role in synaptic phagocytosis,and inhibiting this process could be a new strategy for treating traumatic brain injury.
文摘The fuorescence-based in vivo flow cytometry(IVFC)is an emerging tool to monitor eirculating cells in vivo.As a noninvasive and real-timne diagnostic technology,the fluorescence based IVFC allows long-term monitoring of circulating cells without changing their native biological environment.It has been applied for various biological applications(eg,monitoring circulating tumor cells).In this work,we will review our recent works on fluorescence-based IVFC.The operation principle and typical biological applications will be introduced.In addition,the recent advances in IVFC flow cytometry based on photoacoustic effects and other label free detection methods such as imaging based methods,difuse-light methods,hybrid multimodality methods and multispectral methods are also summarized.
基金supported by grants awarded by the National Major Scientic Research Program of China(Grant No.2011CB910404)the National Nature Science Foundation of China(Grant No.61227017)+1 种基金the State Key Basic Research Development Program of China(2012CB518103)National Outstanding Young Scientist Award of China(61425006).
文摘Alzheimers disease(AD)is a chronic neurodegenerative disease.The symptoms include memoryand spatial learning dificulties,language disorders,and loss of motivation,which get worse overtime,eventually ending in death.No ffective treatments are available for AD,currently.Currenttreatments only attenuate symptoms temporarily and are associated with severe side ffects.Nearinfra-red(NIR)light has been studied for a long time.We investigated the effect of NIR on ADusing a transgenic mouse model,which was obtained by co-injecting two vectors carrying ADmutations in amyloid precursor protein(APP)and presenilin-i(PSEN1)into C57BL/6J mice.The irradiation equipment consisted of an accommodating box and an LED array.The wave-length of NIR light emitted from LED was between 1040 nm and 1090 nm.The power densitydelivered at the level of the mice was approximately 15 mW/cm^(2),Firstly,we treated the micewith NIR for 40 days,Then,the irradiation was suspended for 28 days.Finally,another 15 daystreatment was brought to mice.We conducted Morris water maze and immunofluorescenceanalysis to evaluate the effects of treatment.Immunofuorescence analysis was based on mea-suring the quantity of plaques in mouse brain slices,Our results show that NIR light improvesmemory and spatial learning ability and reduces plaques moderately.NIR light represents apotential treatment for AD.
基金supported by the National Natural Science Foundation of China,Nos.81802232(to JXW),81801170(to YHT),82071284(to YHT),2019YFA0112000(to YHT)the Scientific Research and Innovation Program of Shanghai Education Commission,No.2019-01-07-00-02-E00064(to GYY)+1 种基金Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission,No.20JC1411900(to GYY)Science and Technology Commission of Shanghai,No.19441907900(to JFS).
文摘Blood-brain barrier(BBB)disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke.Reducing this disruption has therapeutic potential.Transcranial focused ultrasound stimulation has shown neuromodulatory and neuroprotective effects in various brain diseases including ischemic stroke.Ultrasound stimulation can reduce inflammation and promote angiogenesis and neural circuit remodeling.However,its effect on the BBB in the acute phase of ischemic stroke is unknown.In this study of mice subjected to middle cerebral artery occlusion for 90 minutes,low-intensity low-frequency(0.5 MHz)transcranial focused ultrasound stimulation was applied 2,4,and 8 hours after occlusion.Ultrasound stimulation reduced edema volume,improved neurobehavioral outcomes,improved BBB integrity(enhanced tight junction protein ZO-1 expression and reduced IgG leakage),and reduced secretion of the inflammatory factors tumor necrosis factor-αand activation of matrix metalloproteinase-9 in the ischemic brain.Our results show that low-intensity ultrasound stimulation attenuated BBB disruption and edema formation,which suggests it may have therapeutic use in ischemic brain disease as a protector of BBB integrity.
基金This work is supported by the Cross Research Fund of Biomedical Engineering of Shanghai Jiao Tong University(YG2019QNA43).
文摘Catalysis-based chemodynamic therapy(CDT)is an emerging cancer treatment strategy which uses a Fenton-like reaction to kill tumor cells by catalyzing endogenous hydrogen peroxide(H_(2)O_(2))into a toxic hydroxyl radical(·OH).The performance of CDT is greatly dependent on PDT agent.Herein,mitochondria-targeting Pt nanoclusters were synthesized using cytochrome c aptamer(CytcApt)as template.The obtained CytcApt-PtNCs can produce.OH by H_(2)O_(2)under the acidic conditions.Moreover,CytcApt-PtNCs could kill 4T1 tumor cells in a pH-dependent manner,but had no side effect on normal 293T cells.Therefore,CytcApt-PtNCs possess excellent therapeutic effect and good biosafety,indicating their great potential for CDT.
基金the National Science Fund for Distinguished Young Scholars(Grant No.61425006)Program of Shanghai Technology Research Leader(Grant No.17XD1402200).
文摘Recent studies in oncology have addressed the importance of detecting circulating tumor cell clusters because circulating tumor cell clusters might survive and metastasize more easily than single circulating tumor cells.Signals with larger peak widths detected by in vivo flow cytometer(IVFC)have been used to identify cell clusters in previous studies.However,the accuracy of this criterion might be greatly degraded by variance in blood°ow and the rolling behaviors of circulating tumor cells.Here,we propose a criterion and algorithm to distinguish cell clusters from single cells.In this work,we first used area-based and volume-based models for single°uorescent cells.Simulating each model,we analyzed the corresponding morphology of IVFC signals from cell clusters.According to the Rayleigh criterion,the valley between two adjacent peak signals from two distinguishable cells should be lower than 73.5%of the peak values.A novel signal processing algorithm for IVFC was developed based on this criterion.The results showed that cell clusters can be reliably identied using our proposed algorithm.Intravital imaging was also performed to further support our algorithm.With enhanced accuracy,IVFC is a powerful tool to study circulating cell clusters.
基金the grants of the National Major Scientific Research Program of China(Grant Nos.2011CB910404 and 2012CB966801)the National N ature Science Foundation of China(Grant No.61227017)the National Science Fund for Distinguished Young Scholars(Grant No.61425006).
文摘In biomedical research fields,the in vio Aow cytometry(IVFC)is a widely used technology which is able to monitor target cells dynamically in living animals.Although the setup of IVFC system has been well established,baseline drift is still a challenge in the process of quantifying circulating cells.Previous methods,i.e.,the dynamic peak picking method,counted cells by setting a static threshold without considering the baseline drift,leading to an inaccurate cell quantification.Here,we developed a method of cell counting for IVFC data with baseline drift by interpolation fitting,automatic segmentation and wavelet-based denoising.We demonstrated its performance for IVFC signals with three types of representative baseline drift.Compared with non-baseline correction methods,this method showed a higher sensitivity and specificity,as well as a better result in the Pearson's correlation coefficient and the mean-squared error(MSE).
基金supported by the National Major Scientic Research Program of China(Grant No.2011CB910404)the National Nature Science Foundation of China(Grant Nos.61227017,31400772 and 81273215)+3 种基金the National Science Fund for Distinguished Young Scholars(Grant No.61425006)the grants of the Project for Laureate of Taishan Scholar(Grant No.ts201511075)the Innovation Project of Shandong Academy of Medical Sciences,the Projects of medical and health technology development program in Shandong province(No.2015WS0194)the science and technology program from Shandong Academy of Medical Sciences(No.2015-25).
文摘T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an initial signal of T-cell activation,has been found to occur before IS for-mation.The mechanism for triggering the calcium signaling and relationship bet ween calciumrelease and IS format ion remains unclear.Herein,using live-cell imaging,we found that int ercellularadhesion molecule 1(ICAM-1),an essential mdlecule for IS formation,accumulated and then wasdepleted at the center of the synapse before complete IS formation.During the proces of ICAM1depletion,calcium was released.if ICAM-1 failed to be depleted from the center of the synapse,thesustained calcium signaling could not be induced.Moreover,depletion of ICAM-1 in ISs preferen-tially ccurred with the contact of antigen-specific T-cels and dendritic clls(DCs).Blocking thebinding ofICA M-1 and lymphocy te finction-associated antigen 1(LFA-1),ICAM-1 failed to depleteat the center of the synapse,and calcium release in T-clls decreased.In studying the mechanism ofhow the depletion ofiCA M1 could influence calcium release in T-clls,we found that the movementof ICAM-1 was associat ed with the localization of LFA-1 in the IS,which afected the localization ofcalcium microdomains,ORAIl and mitochondria in IS.Therefore,the depletion of ICAM-1 in the center of the synapse is an important factor for an initial sust ained calcium release in T-cells.
基金supported by grants from the National Key R&D Program of China(2019YFA0112000)Zhejiang Provincial Natural Science Foundation of China(No.LQ21H300009)+1 种基金National Natural Science Foundation of China(81930051,82003658,82202785)GuangCi Professorship Program of Ruijin Hospital Shanghai Jiao Tong University School of Medicine.
文摘Dear Editor,Nanotechnology-based therapeutic strategies have been proven effective in diseases including cancer,infection,inflammation,etc.1 However,the application of nanotechnology is greatly restricted in the treatment of central nervous system(CNS)disorders due to physiological CNS barriers.For example,the blood-brain barrier(BBB)can be the“Maginot line”for pharmacologically active molecules,blocking them out of the CNS.
文摘Stroke is the second most common cause of death in the world especially in the ageing population.1 Thrombolysis and intravascular embolectomy are the main treatment and populated rapidly.23 However,the benefi-ciary is still limited because the mechanistic studies are behind.The basic research on stroke is improved because of new devices,novel techniques and the development of other disciplines.4 The update of a broad range of topics related to stroke is a widely appreciated feature.In order to improve the understanding of cellular and molecular mechanisms of stroke,the 2nd Summit of Chinese Basic Science Research on Stroke 2018 has been held in Beijing,China.
基金support from Harvard/MITsupport by grants from the National Key R&D Program of China(2019YFA0112000)+5 种基金National Natural Science Foundation of China(Nos.81930051,82003658,81801170)the Interdisciplinary Program of Shanghai Jiao Tong University(ZH2018ZDA04,China)Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support(20171906,China)China Postdoctoral Science Foundation(2019M661546)National Postdoctoral Program for Innovative Talents(BX20200212,China)Zhejiang Provincial Natural Science Foundation of China(No.LQ21H300009,China)。
文摘Central nervous system(CNS)injuries,including stroke,traumatic brain injury,and spinal cord injury,are essential causes of death and long-term disability and are difficult to cure,mainly due to the limited neuron regeneration and the glial scar formation.Herein,we apply extracellular vesicles(EVs)secreted by M2 microglia to improve the differentiation of neural stem cells(NSCs)at the injured site,and simultaneously modify them with the injured vascular targeting peptide(DA7R)and the stem cell recruiting factor(SDF-1)on their surface via copper-free click chemistry to recruit NSCs,inducing their neuronal differentiation,and serving as the nanocarriers at the injured site(Dual-EV).Results prove that the Dual-EV could target human umbilical vascular endothelial cells(HUVECs),recruit NSCs,and promote the neuronal differentiation of NSCs in vitro.Furthermore,10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis,and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs,miR30b-3p,miR-222-3p,miR-129-5p,and miR-155-5p may exert effect of inducing NSC to differentiate into neurons.In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice,potentiate NSCs recruitment,and increase neurogenesis.This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells,and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health.
文摘Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially successful in regressing prostate tumors, the disease ultimately comes back as castration-resistant prostate cancer (CRPC) or at the late stage as neuroendocrine prostate cancer (NEPC). CRPC remains largely dependent on hyperactive AR signaling in the milieu of low androgen, while NEPC is negative of AR expression but positive of many AR-repressed genes. Recent technological advances in genome-wide analysis of transcription factor binding sites have revealed an unprecedented set of AR target genes. In addition to its well-known function in activating gene expression, AR is increasingly known to also act as a transcriptional repressor. Here, we review the molecular mechanisms by which AR represses gene expression. We also summarize AR-repressed genes that are aberrantly upregulated in CRPC and NEPC and represent promising targets for therapeutic intervention.
基金This work was supported by the Natural Science Foundation of China(61805135)the National Key Research and Development Program of China(2019YFC1604604)+2 种基金Shanghai Jiao Tong University(ZH2018QNA43)the Science and Technology Commission of Shanghai Municipality(19DZ2280300)the Innovation Research Plan supported by Shanghai Municipal Education Commission(ZXWF082101).
文摘Photodynamic therapy(PDT),which utilizes light excite photosensitizers(PSs)to generate reactive oxygen species(ROS)and consequently ablate cancer cells or diseased tissue,has attracted a great deal of attention in the last decades due to its unique advantages.However,the advancement of PDT is restricted by the inherent characteristics of PS and tumor microenvironment(TME).It is urgent to explore high-performance PSs with TME regulation capability and subsequently improve the therapeutic outcomes.Herein,we reported a newly engineered PS of polymer encapsulated carbonized hemin nanoparticles(P-CHNPs)via a facile synthesis procedure for boosting photodynamic anticancer therapy.Solvothermal treatment of hemin enabled the synthesized P-CHNPs to enhance oxidative stress in TME,which could be further amplified under light irradiation.Excellent in vitro and in vivo PDT effects were achieved due to the improved ROS(hydroxyl radicals and singlet oxygen)generation efficiency,hypoxia relief,and glutathione depletion.Moreover,the superior in vitro and in vivo biocompatibility and boosted PDT effect make the P-CHNPs a potential therapeutic agent for future translational research.
基金the National Key Research and Development Program of China(Grant No.2019YFC1604604)the National Science Fund for Distinguished Young Scholars(Grant No.61425006)+2 种基金the SJTU Medicine Engineering Interdisciplinary Research Fund(Grant No.YG2017MS19)the Program of Shanghai Technology Research Leader(Grant No.17XD1402200)the Fundamental Research Funds for the Central Universities,and the National Natural Science Foundation of China(Grant No.81661168014,61975118 and 62075013).
文摘Circulating tumor cells(CTCs)is an established biomarker of cancer metastasis.The circulation dynamics of CTCs are important for understanding the mechanisms underlying tumor cell dissemination.Although studies have revealed that the circadian rhythm may disrupt the growth of tumors,it is generally unclear whether the circadian rhythm controls the release of CTCs.In clinical examinations,the current in vitro methods for detecting CTCs in blood samples are based on a fundamental assumption that CTC counts in the peripheral blood do not change significantly over time,which is being challenged by recent studies.Since it is not practical to draw blood from patients repeatedly,a feasible strategy to investigate the circadian rhythm of CTCs is to monitor them by in vivo detection methods.Fluoresce nee in vivo flow cytometry(IVFC)is a powerful optical technique that is able to detect fluoresce nt circulating cells directly in living animals in a noninvasive manner over a long period of time.In this study,we applied fluorescence IVFC to monitor CTCs noninvasively in an orthotopic mouse model of human prostate cancer.We observed that CTCs exhibited stochastic bursts over cancer progression.The probability of the bursting activity was higher at early stages than at late stages.We longitudinally monitored CTCs over a 24-h period,and our results revealed striking daily oscillations in CTC counts that peaked at the onset of the night(active phase for rodents),suggesting that the release of CTCs might be regulated by the circadian rhythm.
文摘Dear Editor,We thank Niedre et al.for their correspondence regarding our recent paper1.They proposed a point that the temporal distribution of circulating tumor cells(CTCs)monitored by diffuse in vivo flow cytometry in a multiple myeloma mouse model in their previous work2 might be different from our results.Niedre et al.claimed that CTC detection statistics deviated from Poisson but did not found circadian variations in CTC numbers in a multiple myeloma mouse model.They also cite another literature by Juratli.et al.3,in which the authors reported that CTC numbers did not always correlate with tumor size during cancer progression.However,by establishing an orthotopic mouse model of prostate cancer and utilizing the technology in vivo flow cytometry(IVFC),we found CTCs exhibited bursting activity and daily oscillation in an orthotopic model of prostate cancer.
基金This work was supported by grants from the National Key Research and Development Program of China(Grant No.2019YFC1604604)the Special Fund for Research on National Major Research Instruments of China(Grant No.62027824)+5 种基金the National Science Fund for Distinguished Young Scholars(Grant No.61425006)the SJTU Medicine Engineering Interdisciplinary Research Fund(Grant No.YG2017MS19)the Program of Shanghai Technology Research Leader(Grant No.17XD1402200)the Fundamental Research Funds for the Central Universities(Grant No.81661168014)the project of Innovative Research Team of High-level Local Universities in Shanghai,Talents Program of Shanghai Municipal Health Commission(Chen Liang,Grant No.2018BR06)the National Natural Science Foundation of China(Grant No.92068111,81973272,82073836,61975118,and 62075013).
文摘Photobiomodulation,by utilizing low-power light in the visible and near-infrared spectra to trigger biological responses in cells and tissues,has been considered as a possible therapeutic strategy for Alzheimer’s disease(AD),while its specific mechanisms have remained elusive.Here,we demonstrate that cognitive and memory impairment in an AD mouse model can be ameliorated by 1070-nm light via reducing cerebralβ-amyloid(Aβ)burden,the hallmark of AD.The glial cells,including microglia and astrocytes,play important roles in Aβclearance.Our results show that 1070-nm light pulsed at 10 Hz triggers microglia rather than astrocyte responses in AD mice.The 1070-nm lightinduced microglia responses with alteration in morphology and increased colocalization with Aβare sufficient to reduce Aβload in AD mice.Moreover,1070-nm light pulsed at 10 Hz can reduce perivascular microglia and promote angiogenesis to further enhance Aβclearance.Our study confirms the important roles of microglia and cerebral vessels in the use of 1070-nm light for the treatment of AD mice and provides a framework for developing a novel therapeutic approach for AD.
基金This work was supported by NSFC project 81070939(G-YY)and U1232205(G-YY).
文摘Stroke is the second leading cause of mortality and morbidity worldwide.Early intervention is of great importance in reducing disease burden.Since the conventional risk factors cannot fully account for the pathogenesis of stroke,it is extremely important to detect useful biomarkers of the vascular disorder for appropriate intervention.Arterial stiffness,a newly recognised reliable feature of arterial structure and function,is demonstrated to be associated with stroke onset and serve as an independent predictor of stroke incidence and poststroke functional outcomes.In this review article,different measurements of arterial stiffness,especially pressure wave velocity,were discussed.We explained the association between arterial stiffness and stroke occurrence by discussing the secondary haemodynamic changes.We reviewed clinical data that support the prediction role of arterial stiffness on stroke.Despite the lack of long-term randomised double-blind controlled therapeutic trials,it is high potential to reduce stroke prevalence through a significant reduction of arterial stiffness(which is called de-stiffening therapy).Pharmacological interventions or lifestyle modification that can influence blood pressure,arterial function or structure in either the short or long term are promising de-stiffening therapies.Here,we summarised different de-stiffening strategies including antihypertension drugs,antihyperlipidaemic agents,chemicals that target arterial remodelling and exercise training.Large and well-designed clinical trials on de-stiffening strategy are needed to testify the prevention effect for stroke.Novel techniques such as modern microscopic imaging and reliable animal models would facilitate the mechanistic analyses in pathophysiology,pharmacology and therapeutics.
基金supported by the National Natural Science Foundation of China (81773283)。
文摘Platelets buoy up cancer metastasis via arresting cancer cells, enhancing their adhesion, and facilitating their extravasation through the vasculature. When deprived of intracellular and granular contents, platelet decoys could prevent metastatic tumor formation. Inspired by these, we developed nanoplatesomes by fusing platelet membranes with lipid membranes(P-Lipo) to restrain metastatic tumor formation more efficiently. It was shown nanoplateletsomes bound with circulating tumor cells(CTC)efficiently, interfered with CTC arrest by vessel endothelial cells, CTC extravasation through endothelial layers, and epithelial-mesenchymal transition of tumor cells as nanodecoys. More importantly, in the mouse breast tumor metastasis model, nanoplateletsomes could decrease CTC survival in the blood and counteract metastatic tumor growth efficiently by inhibiting the inflammation and suppressing CTC escape. Therefore, nanoplatelesomes might usher in a new avenue to suppress lung metastasis.
基金the National Natural Science Foundation of China(Nos.50779033,81771244,81771251,81471178 and 81522015)the National Key Research and Development Program of China(No.2016YFC1300600)+1 种基金the K.C.Wong Education Foundationthe Fund of the Science and Technology Commission of Shanghai Municipality(No.17ZR1413600)
文摘Diabetes is usually associated with cerebrovascular disease,especially stroke.In practice,fasudil is widely accepted to be applied for the treatment of vascular disease.This article demonstrates the study concentrating on the effects of fasudil pretreatment on the prognosis of diabetic stroke.250—300 g SpragueDawley rats were randomly divided into three groups,non-diabetic stroke group,diabetic stroke group,and fasudil pretreatment group.The rats of diabetes group were treated with intraperitoneal injection of streptozotocin(60 mg/kg),in the meantime the same dose of citrate buffer was injected into those of the control group.The rats of the fasudil group received daily fasudil intraperitoneal injection at 10 mg/kg for three consecutive weeks.After four weeks,all the rats of the experimental group were treated with middle cerebral artery occlusion for 90 min.After sacrifice,the fresh brain samples were collected for following experiments,including infarct volume,edema volume,blood-brain barrier(BBB),which were detected by immunohistochemistry.Inflammatory factors were examined by real-time polymerase chain reaction(RT-PCR)using tissue Ribonucleic Acid(RNA).The concentration of blood glucose is 15 mmol/L or more,which proved that the diabetes model was a success.Fasudil pretreatment decreases the percentage of stroke mortality of diabetes from 43.75%to 31.25%,while the infarction volume decreases from 52.95%±12.7%to 45.97%±6.7%.Gap formation of tight junction and Immunoglobulin G(Ig G)leakage were reduced(P<0.05),and the expression of inflammatory factors decreases(P<0.05)in fasudil pretreatment after diabetic stroke.Diabetes aggravates the mortality of cerebral ischemic rats.Prolonged fasudil pretreatment can reduce mortality of diabetic stroke,decrease cerebral infarction volume and undermine inflammatory factors expression,and protect the BBB.
基金This study was supported by grants from the National Key Research and Development Program of China(2016YFC1300600)the National Natural Science Foundation of China(81471178,GYY,81522015,YTW,81771251,GYY,81771244,ZJZ)+1 种基金K.C.Wong Education Foundationthe Science and Technology Commission of Shanghai Municipality(17ZR1413600,ZJZ).
文摘MicroRNA-126 was involved in angiogenesis during physiological and pathological process. It was mainly expressed in endothelial cells, and defined as a pivotal biological molecule associated with vascular disease. Increased microRNA-126 in endothelial cells promotes angiogenesis in ischemic stroke, repairs impaired endothelial cells in atherosclerosis, and attenuates vascular dysfunction in diabetics. By contrast, microRNA-126 transferred from endothelial cell to smooth muscle cells could lead to proliferation that induced intimal hyperplasia. Additionally, microRNA-126 could be a tumor suppressor or an oncogene, which was depended on the cancer type. In this review, we summarized the function of microRNA-126 in ischemic stroke, atherosclerosis, diabetics, tumor, and discussed the underlying mechanisms.