Multiple roles of glycogen synthase kinase-3（GSK-3）in neural tissues：GSK-3 is a serine/threonine kinase that has two isoforms encoded by two different genes,GSK-3αand GSK-3β,in mammals.GSK-3 has several sites of ...Multiple roles of glycogen synthase kinase-3（GSK-3）in neural tissues：GSK-3 is a serine/threonine kinase that has two isoforms encoded by two different genes,GSK-3αand GSK-3β,in mammals.GSK-3 has several sites of serine and tyrosine phosphorylation.展开更多
Nanocarrier-based drug delivery systems(nDDSs)present significant opportunities for improving disease treatment,offering advantages in drug encapsulation,solubilization,stability enhancement,and optimized pharmacokine...Nanocarrier-based drug delivery systems(nDDSs)present significant opportunities for improving disease treatment,offering advantages in drug encapsulation,solubilization,stability enhancement,and optimized pharmacokinetics and biodistribution.n DDSs,comprising lipid,polymeric,protein,and inorganic nanovehicles,can be guided by or respond to biological cues for precise disease treatment and management.Equipping nanocarriers with tissue/celltargeted ligands enables effective navigation in complex environments,while functionalization with stimuli-responsive moieties facilitates site-specific controlled release.These strategies enhance drug delivery efficiency,augment therapeutic efficacy,and reduce side effects.This article reviews recent strategies and ongoing advancements in n DDSs for targeted drug delivery and controlled release,examining lesion-targeted nanomedicines through surface modification with small molecules,peptides,antibodies,carbohydrates,or cell membranes,and controlled-release nanocarriers responding to endogenous signals such as pH,redox conditions,enzymes,or external triggers like light,temperature,and magnetism.The article also discusses perspectives on future developments.展开更多
Spinal cord injury（SCI）frequently results in the permanent loss of function below the level of injury due to the failure of axonal regeneration in the adult mammalian central nervous system（CNS）.The limited intrin...Spinal cord injury（SCI）frequently results in the permanent loss of function below the level of injury due to the failure of axonal regeneration in the adult mammalian central nervous system（CNS）.The limited intrinsic growth capacity of adult neurons,a lack of growth-promoting factors and the multifactorial inhibitory microenvironment around the lesion site contribute to the lack of axonalregeneration. Strategies such as transplantation of cells,展开更多
Spinal cord injury （SCI） is an unexpected event that is both devastating and debilitating, resulting in not just motor and sensory loss, but also autonomic dysfunction of the bladder, bowel and sexual organs. Curren...Spinal cord injury （SCI） is an unexpected event that is both devastating and debilitating, resulting in not just motor and sensory loss, but also autonomic dysfunction of the bladder, bowel and sexual organs. Currently, there are no treatments available to improve outcome follow- ing SCI, leaving individuals with permanent and lifelong physical disability. Worldwide it is estimated that more than 500,000 people sustain a SCI each year, with average lifetime cost of paraplegia and quadriplegia estimated at $5 million and $9.5 million respectively. We therefore urgently need effective therapies to improve quality of life following SCI, and this requires a greater understanding of how cell and axonal injury develops after the traumatic event.展开更多
AIM：To investigate the effect of tissue factor targeting peptide（TF-TP）on retinal pigment epithelium（RPE）cells tight junctions.METHODS：Cell counting kit-8（CCK-8）was used to measure the proliferation of ARPE-19...AIM：To investigate the effect of tissue factor targeting peptide（TF-TP）on retinal pigment epithelium（RPE）cells tight junctions.METHODS：Cell counting kit-8（CCK-8）was used to measure the proliferation of ARPE-19 cells.Expression of tight junction,ZO-1 in ARPE-19 cells was measured by Western blot and immunofluorescent staining.Western blot was also used to detect the expression of tissue factor（TF）.CEC Transmigration Assay was used to measure the migration of ARPE-19 cells.The transport of fluorescent markers [fluorescein isothiocyanate dextrans of 4,10,20（FD4,FD10,FD20） ]and the transepithelial electrical resistance（TEER）were used to measure in ARPE-19 cell RESULTS：CCK-8 assay showed that 5μmol/L TF-TP can inhibit ARPE-19 cells abnormally proliferation stimulated by lipopolysaccharide（LPS;P〈0.05）.LPS increased the transport of fluorescent markers（FD4,FD10,FD20）and decreased TEER levels in ARPE-19 cells,respectively,which were prevented by 5μmol/L TF-TP pretreatment（P〈0.05）. Furthermore,LPS significantly up-regulated the expression of TF and downregulated the expression of ZO-1（P〈0.05）in ARPE-19 cell which was inhibited by the TF-TP（P〈0.05）.In addition,TF-TP inhibited the abnormal migration induced by LPS in ARPE-19 cell（P〈0.05）.CONCLUSION：Our findings suggest that TF-TP suppressed proliferation and migration of ARPE-19 cells induced by LPS,and maintained the RPE tight junctions through inhibition of TF expression and increased expression of ZO-1.展开更多
Insulin resistance(IR)is associated with several metabolic disorders,including type 2 diabetes(T2D).The development of IR in insulin target tissues involves genetic and acquired factors.Persons at genetic risk for T2D...Insulin resistance(IR)is associated with several metabolic disorders,including type 2 diabetes(T2D).The development of IR in insulin target tissues involves genetic and acquired factors.Persons at genetic risk for T2D tend to develop IR several years before glucose intolerance.Several rodent models for both IR and T2D are being used to study the disease pathogenesis;however,these models cannot recapitulate all the aspects of this complex disorder as seen in each individual.Human pluripotent stem cells(hPSCs)can overcome the hurdles faced with the classical mouse models for studying IR.Human induced pluripotent stem cells(hiPSCs)can be generated from the somatic cells of the patients without the need to destroy a human embryo.Therefore,patient-specific hiPSCs can generate cells genetically identical to IR individuals,which can help in distinguishing between genetic and acquired defects in insulin sensitivity.Combining the technologies of genome editing and hiPSCs may provide important information about the genetic factors underlying the development of different forms of IR.Further studies are required to fill the gaps in understanding the pathogenesis of IR and diabetes.In this review,we summarize the factors involved in the development of IR in the insulin-target tissues leading to diabetes.Also,we highlight the use of hPSCs to understand the mechanisms underlying the development of IR.展开更多
Objective： To investigate the effects of Huanglian Jiedu Decoction （黄连解毒汤, HLJDD） on glucose transporter 4 （GLUT4） protein expressions in insulin-resistant murine target tissues. Methods： The experimental m...Objective： To investigate the effects of Huanglian Jiedu Decoction （黄连解毒汤, HLJDD） on glucose transporter 4 （GLUT4） protein expressions in insulin-resistant murine target tissues. Methods： The experimental male Wistar rats were established into insulin resistant models by injecting streptozotocin （STZ 30 mg/kg） via caudal vein and feeding them with high fat high caloric diet, and randomly divided into the model group, the aspirin group and the HLJDD group. Besides, a normal group was set up for control. Changes of body weight （BW）, levels of serum fasting blood glucose （FBG）, serum fasting insulin （FINS） and oral glucose tolerance test （OGTT） were routinely determined. The expression of GLUT4 protein in adipose and skeletal muscle tissues before and after insulin stimulation was determined with Western blot. Results： In the HLJDD group after treatment, BW and FBG got decreased, OGTT improved, and the expression and translocation of GLUT4 protein elevated obviously, either before or after insulin stimulation, as compared with those in the model group, showing significant differences respectively. Conclusion： The mechanism of improving insulin resistance by HLJDD is probably associated with its effect in elevating GLUT4 protein expression and translocation in adipose and skeletal muscle tissues of insulin resistant rats.展开更多
Increasing the proximity of microelectrode arrays(MEA)to targeted neural tissues can establish efficient neural interfaces for both recording and stimulation applications.This has been achieved by constructing protrud...Increasing the proximity of microelectrode arrays(MEA)to targeted neural tissues can establish efficient neural interfaces for both recording and stimulation applications.This has been achieved by constructing protruding three-dimensional(3D)structures on top of conventional planar microelectrodes via additional micromachining steps.However,this approach adds fabrication complexities and limits the 3D structures to certain shapes.We propose a one-step fabrication of MEAs with versatile microscopic 3D structures via“microelectrothermoforming(μETF)”of thermoplastics,by utilizing 3D-printed molds to locally deform planar MEAs into protruding and recessing shapes.Electromechanical optimization enabled a 3D MEA with 80μm protrusions and/or recession for 100μm diameter.Its simple and versatile shaping capabilities are demonstrated by diverse 3D structures on a single MEA.The benefits of 3D MEA are evaluated in retinal stimulation through numerical simulations and ex vivo experiments,confirming a threshold lowered by 1.7 times and spatial resolution enhanced by 2.2 times.展开更多
In vitro evaluation of novel therapeutic approaches often fails to reliably predict efficacy and toxicity,especially when recapitulating conditions involving recirculating cells.Current testing strategies are often ba...In vitro evaluation of novel therapeutic approaches often fails to reliably predict efficacy and toxicity,especially when recapitulating conditions involving recirculating cells.Current testing strategies are often based on static co-culturing of cells in suspension and 3D tissue models,where cell sedimentation on the target tissue can occur.The observed effects may then mostly be a consequence of sedimentation and of the corresponding forced cell-tissue interactions.The realization of continuous medium flow helps to better recapitulate physiological conditions and cell-tissue interactions.To tackle current limitations of perfused organ-on-chip approaches,we developed a microfluidic chip and operation concept,which prevents undesired sedimentation and accumulation of suspended cells during multiple days by relying on gravity-driven perfusion.Our platform,which we termed“human immune flow(hiFlow)chip”,enables to co-culture cells in suspension with up to 7 preformed microtissue models.Here,we present the design principle and operation of the platform,and we validate its performance by culturing cells and microtissues of a variety of different origins.Cells and tissues could be monitored on chip via high-resolution microscopy,while cell suspensions and microtissues could be easily retrieved for off-chip analysis.Our results demonstrate that primary immune cells and a range of different spheroid models of healthy and diseased tissues can be maintained for over 6 days on chip.As proof-of-concept cell-tissue interaction assay,we used an antibody treatment against diffuse midline glioma,a highly aggressive pediatric tumor.We are confident that our platform will help to increase the prediction power of in vitro preclinical testing of novel therapeutics that rely on the interaction of circulating cells with organ tissues.展开更多
文摘Multiple roles of glycogen synthase kinase-3（GSK-3）in neural tissues：GSK-3 is a serine/threonine kinase that has two isoforms encoded by two different genes,GSK-3αand GSK-3β,in mammals.GSK-3 has several sites of serine and tyrosine phosphorylation.
基金supported by the National Natural Science Foundation of China(No.82273876)the Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions of China(No.171028)+1 种基金the Project of State Key Laboratory of Advanced Drug Delivery and Release Systems(No.DSQZZD-200301)the Fundamental Research Fund for the Central Universities(No.2632022YC02)。
文摘Nanocarrier-based drug delivery systems(nDDSs)present significant opportunities for improving disease treatment,offering advantages in drug encapsulation,solubilization,stability enhancement,and optimized pharmacokinetics and biodistribution.n DDSs,comprising lipid,polymeric,protein,and inorganic nanovehicles,can be guided by or respond to biological cues for precise disease treatment and management.Equipping nanocarriers with tissue/celltargeted ligands enables effective navigation in complex environments,while functionalization with stimuli-responsive moieties facilitates site-specific controlled release.These strategies enhance drug delivery efficiency,augment therapeutic efficacy,and reduce side effects.This article reviews recent strategies and ongoing advancements in n DDSs for targeted drug delivery and controlled release,examining lesion-targeted nanomedicines through surface modification with small molecules,peptides,antibodies,carbohydrates,or cell membranes,and controlled-release nanocarriers responding to endogenous signals such as pH,redox conditions,enzymes,or external triggers like light,temperature,and magnetism.The article also discusses perspectives on future developments.
基金Supported by grants from the Deutsche Forschungsgemeinschaft(BL414/3-1)International Foundation for Research in Paraplegia+2 种基金the Indiana University Health-Indiana University School of Medicine Strategic Research InitiativeIndiana Spinal Cord and Brain Injury Research FundMorton Cure Paralysis Fund to AB and a Heinz Gotze Memorial Fellowship to SL
文摘Spinal cord injury（SCI）frequently results in the permanent loss of function below the level of injury due to the failure of axonal regeneration in the adult mammalian central nervous system（CNS）.The limited intrinsic growth capacity of adult neurons,a lack of growth-promoting factors and the multifactorial inhibitory microenvironment around the lesion site contribute to the lack of axonalregeneration. Strategies such as transplantation of cells,
基金supported by the Neil Sachse Foundation,Australia,a philanthropic organisation supporting research into spinal cord injury
文摘Spinal cord injury （SCI） is an unexpected event that is both devastating and debilitating, resulting in not just motor and sensory loss, but also autonomic dysfunction of the bladder, bowel and sexual organs. Currently, there are no treatments available to improve outcome follow- ing SCI, leaving individuals with permanent and lifelong physical disability. Worldwide it is estimated that more than 500,000 people sustain a SCI each year, with average lifetime cost of paraplegia and quadriplegia estimated at $5 million and $9.5 million respectively. We therefore urgently need effective therapies to improve quality of life following SCI, and this requires a greater understanding of how cell and axonal injury develops after the traumatic event.
基金Supported by Science and Technology Project of Guangzhou City(No.2014J4100035)the Project of the Third Affiliated Hospital of Guangzhou Medical University(No.2013Y06)
文摘AIM：To investigate the effect of tissue factor targeting peptide（TF-TP）on retinal pigment epithelium（RPE）cells tight junctions.METHODS：Cell counting kit-8（CCK-8）was used to measure the proliferation of ARPE-19 cells.Expression of tight junction,ZO-1 in ARPE-19 cells was measured by Western blot and immunofluorescent staining.Western blot was also used to detect the expression of tissue factor（TF）.CEC Transmigration Assay was used to measure the migration of ARPE-19 cells.The transport of fluorescent markers [fluorescein isothiocyanate dextrans of 4,10,20（FD4,FD10,FD20） ]and the transepithelial electrical resistance（TEER）were used to measure in ARPE-19 cell RESULTS：CCK-8 assay showed that 5μmol/L TF-TP can inhibit ARPE-19 cells abnormally proliferation stimulated by lipopolysaccharide（LPS;P〈0.05）.LPS increased the transport of fluorescent markers（FD4,FD10,FD20）and decreased TEER levels in ARPE-19 cells,respectively,which were prevented by 5μmol/L TF-TP pretreatment（P〈0.05）. Furthermore,LPS significantly up-regulated the expression of TF and downregulated the expression of ZO-1（P〈0.05）in ARPE-19 cell which was inhibited by the TF-TP（P〈0.05）.In addition,TF-TP inhibited the abnormal migration induced by LPS in ARPE-19 cell（P〈0.05）.CONCLUSION：Our findings suggest that TF-TP suppressed proliferation and migration of ARPE-19 cells induced by LPS,and maintained the RPE tight junctions through inhibition of TF expression and increased expression of ZO-1.
基金the Qatar National Research Fund,No.NPRP10-1221-160041.
文摘Insulin resistance(IR)is associated with several metabolic disorders,including type 2 diabetes(T2D).The development of IR in insulin target tissues involves genetic and acquired factors.Persons at genetic risk for T2D tend to develop IR several years before glucose intolerance.Several rodent models for both IR and T2D are being used to study the disease pathogenesis;however,these models cannot recapitulate all the aspects of this complex disorder as seen in each individual.Human pluripotent stem cells(hPSCs)can overcome the hurdles faced with the classical mouse models for studying IR.Human induced pluripotent stem cells(hiPSCs)can be generated from the somatic cells of the patients without the need to destroy a human embryo.Therefore,patient-specific hiPSCs can generate cells genetically identical to IR individuals,which can help in distinguishing between genetic and acquired defects in insulin sensitivity.Combining the technologies of genome editing and hiPSCs may provide important information about the genetic factors underlying the development of different forms of IR.Further studies are required to fill the gaps in understanding the pathogenesis of IR and diabetes.In this review,we summarize the factors involved in the development of IR in the insulin-target tissues leading to diabetes.Also,we highlight the use of hPSCs to understand the mechanisms underlying the development of IR.
基金National Natural Science Foundation of P. R. China (No. 30371816)Specialized Research Fund for the Doctoral Program of Higher Education (No. 20030487008)
文摘Objective： To investigate the effects of Huanglian Jiedu Decoction （黄连解毒汤, HLJDD） on glucose transporter 4 （GLUT4） protein expressions in insulin-resistant murine target tissues. Methods： The experimental male Wistar rats were established into insulin resistant models by injecting streptozotocin （STZ 30 mg/kg） via caudal vein and feeding them with high fat high caloric diet, and randomly divided into the model group, the aspirin group and the HLJDD group. Besides, a normal group was set up for control. Changes of body weight （BW）, levels of serum fasting blood glucose （FBG）, serum fasting insulin （FINS） and oral glucose tolerance test （OGTT） were routinely determined. The expression of GLUT4 protein in adipose and skeletal muscle tissues before and after insulin stimulation was determined with Western blot. Results： In the HLJDD group after treatment, BW and FBG got decreased, OGTT improved, and the expression and translocation of GLUT4 protein elevated obviously, either before or after insulin stimulation, as compared with those in the model group, showing significant differences respectively. Conclusion： The mechanism of improving insulin resistance by HLJDD is probably associated with its effect in elevating GLUT4 protein expression and translocation in adipose and skeletal muscle tissues of insulin resistant rats.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIT)(NRF-2022R1C1C1010422,RS-2023-00217893,and NRF 2020R1C1C1010505)。
文摘Increasing the proximity of microelectrode arrays(MEA)to targeted neural tissues can establish efficient neural interfaces for both recording and stimulation applications.This has been achieved by constructing protruding three-dimensional(3D)structures on top of conventional planar microelectrodes via additional micromachining steps.However,this approach adds fabrication complexities and limits the 3D structures to certain shapes.We propose a one-step fabrication of MEAs with versatile microscopic 3D structures via“microelectrothermoforming(μETF)”of thermoplastics,by utilizing 3D-printed molds to locally deform planar MEAs into protruding and recessing shapes.Electromechanical optimization enabled a 3D MEA with 80μm protrusions and/or recession for 100μm diameter.Its simple and versatile shaping capabilities are demonstrated by diverse 3D structures on a single MEA.The benefits of 3D MEA are evaluated in retinal stimulation through numerical simulations and ex vivo experiments,confirming a threshold lowered by 1.7 times and spatial resolution enhanced by 2.2 times.
基金the support for flow cytometry and microscopy by the single cell facility(SCF)at the Department of Biosystems Science and Engineering at ETH Zurichfinancially supported by the Innosuisse grant 38880.1 IP-LS.by the“Personalized Health and Related Technologies(PHRT)”of the ETH Domain(Project#2021-351).
文摘In vitro evaluation of novel therapeutic approaches often fails to reliably predict efficacy and toxicity,especially when recapitulating conditions involving recirculating cells.Current testing strategies are often based on static co-culturing of cells in suspension and 3D tissue models,where cell sedimentation on the target tissue can occur.The observed effects may then mostly be a consequence of sedimentation and of the corresponding forced cell-tissue interactions.The realization of continuous medium flow helps to better recapitulate physiological conditions and cell-tissue interactions.To tackle current limitations of perfused organ-on-chip approaches,we developed a microfluidic chip and operation concept,which prevents undesired sedimentation and accumulation of suspended cells during multiple days by relying on gravity-driven perfusion.Our platform,which we termed“human immune flow(hiFlow)chip”,enables to co-culture cells in suspension with up to 7 preformed microtissue models.Here,we present the design principle and operation of the platform,and we validate its performance by culturing cells and microtissues of a variety of different origins.Cells and tissues could be monitored on chip via high-resolution microscopy,while cell suspensions and microtissues could be easily retrieved for off-chip analysis.Our results demonstrate that primary immune cells and a range of different spheroid models of healthy and diseased tissues can be maintained for over 6 days on chip.As proof-of-concept cell-tissue interaction assay,we used an antibody treatment against diffuse midline glioma,a highly aggressive pediatric tumor.We are confident that our platform will help to increase the prediction power of in vitro preclinical testing of novel therapeutics that rely on the interaction of circulating cells with organ tissues.
