Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactiv...Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.展开更多
Lycium barbarum, a traditional Chinese anti-aging herb, has been shown to protect retinal ganglion cells (RGCs) in a rat chronic ocular hypertension (COH) model. Here, we investigated the expression of endothelin-1 (E...Lycium barbarum, a traditional Chinese anti-aging herb, has been shown to protect retinal ganglion cells (RGCs) in a rat chronic ocular hypertension (COH) model. Here, we investigated the expression of endothelin-1 (ET-1), a strong vasoconstrictor, and its receptors, ETA and ETB, in the COH model and assessed the effects of Lycium barbarum on the ET-1 axis. Elevated intraocular pressure (IOP) was induced in the right eye of SD rats using argon laser photocoagulation. (1) The expression of ET-1, ETA and ETB in normal and COH retinas was studied. (2) Some COH rats were fed daily with Lycium barbarum Polysaccharides (LBP) using 1 mg/kg or phosphate-buffered saline (PBS) for 3 weeks (started 1 week before photocoagulation). The effects of LBP on the expression of ET-1 and its receptors, ETA and ETB, in COH retina were evaluated. A semi-quantitative analysis of staining intensity was used to evaluate the expression levels of ET-1, ETA and ETB in retinal vasculature. We found that (1) Under COH condition, the immunoreactivity of ET-1 was increased in retina associated with an increase of ETB receptor immunoreactivity and a decrease of ETA receptor immunoreactivity. (2) After feeding COH rats with LBP, the expression of ET-1 was decreased with an increase of ETA expression and a decrease of ETB expression in the retina, especially in RGCs. (3) By comparing the staining intensity in the vasculature of COH retina in LBP-fed group with PBS-fed group, there was a decrease in the expression of ET-1 and ETA and an increase in ETB. In summary, ET-1 expression was up-regulated in the retina in COH model. LBP could decrease the expression of ET-1 and modulate the expression of its receptors, ETA and ETB, under the condition of COH. The neuroprotective effect of LBP on RGCs might be related to its ability to regulate the ET-1-mediated biological effects on RGCs and retinal vasculature.展开更多
Artemisinin,also called qinghaosu,is originally derived from the sweet wormwood plant(Artemisia annua),which is used in traditional Chinese medicine.Artemisinin and its derivatives(artemisinins)have been widely used f...Artemisinin,also called qinghaosu,is originally derived from the sweet wormwood plant(Artemisia annua),which is used in traditional Chinese medicine.Artemisinin and its derivatives(artemisinins)have been widely used for many years as anti-malarial agents,with few adverse side effects.Interestingly,evidence has recently shown that artemisinins might have a therapeutic value for several other diseases beyond malaria,including cancers,inflammatory diseases,and autoimmune disorders.Neurodegeneration is a challenging age-associated neurological disorder characterized by deterioration of neuronal structures as well as functions,whereas neuroinflammation has been considered to be an underlying factor in the development of various neurodegenerative disorders,including Alzheimer’s disease.Recently discovered properties of artemisinins suggested that they might be used to treat neurodegenerative disorders by decreasing oxidation,inflammation,and amyloid beta protein(Aβ).In this review,we will introduce artemisinins and highlight the possible mechanisms of their neuroprotective activities,suggesting that artemisinins might have therapeutic potential in neurodegenerative disorders.展开更多
Lycium barbarum(LB)is a traditional Chinese medicine that has been demonstrated to exhibit a wide variety of biological functions,such as antioxidation,neuroprotection,and immune modulation.One of the main mechanisms ...Lycium barbarum(LB)is a traditional Chinese medicine that has been demonstrated to exhibit a wide variety of biological functions,such as antioxidation,neuroprotection,and immune modulation.One of the main mechanisms of Alzheimer’s disease is that microglia activated by amyloid beta(Aβ)transform from the resting state to an M1 state and release pro-inflammatory cytokines to the surrounding environment.In the present study,immortalized microglial cells were pretreated with L.barbarum extract for 1 hour and then treated with oligomeric Aβfor 23 hours.The results showed that LB extract significantly increased the survival of oligomeric Aβ-induced microglial cells,downregulated the expression of M1 pro-inflammatory markers(inducible nitric oxide synthase,tumor necrosis factorα,interleukin-6,and interleukin-1β),and upregulated the expression of M2 anti-inflammatory markers(arginase-1,chitinase-like protein 3,and interleukin-4).LB extract also inhibited the oligomeric Aβ-induced secretion of tumor necrosis factorα,interleukin-6,and interleukin-1βin microglial cells.The results of in vitro cytological experiments suggest that,in microglial cells,LB extract can inhibit oligomeric Aβ-induced M1 polarization and concomitant inflammatory reactions,and promote M2 polarization.展开更多
Background:Artesunate(ART),a member of the artemisinin family,possesses multi-properties,including antiinflammation,anti-oxidation,and anti-tumor.ART was recently reported to show anti-neovascularization effect on the...Background:Artesunate(ART),a member of the artemisinin family,possesses multi-properties,including antiinflammation,anti-oxidation,and anti-tumor.ART was recently reported to show anti-neovascularization effect on the cornea,iris,and retina.Compared to the expensive anti-VEGF treatment,this versatile,economical treatment option is attractive in the ophthalmic field.The safety and toxicity profile of ART intravitreal application are in utmost need.Methods:In this study,immortalized microglial(IMG)cells were treated with ART to determine the safe concentrations without inducing overt inflammatory reactions.Reverse transcription-polymerase chain reaction analysis was used to detect the cytokine expressions in IMG cells in response to ART stimulation.Various doses of ART were intravitreally injected into the right eyes of C57BL/6 mice.Retinal function was tested by electroretinogram,and retinal ganglion cell(RGC)survival was evaluated by counting Brn3a stained cells in flat-mounted retinas at 7 days after ART injection.Results:ART below 5μM was safe for IMG cells in vitro.Both 2.5 and 5μM ART treatment increased IL-10 gene expression in IMG cells while not changing IL-1β,IL-6,TNF-α,and Arg-1.In the in vivo study,intravitreal injection of ART below 100μM did not cause deterioration in the retinal function and RGC survival of the mouse eyes,while 1 mM ART treatment significantly attenuated both the scotopic and photopic b-wave amplitudes and impaired RGC survival.In addition,treatment with ART of 25,50,and 100μM significantly decreased TNF-αgene expression while ART of 100μM significantly increased IL-10 in the mouse retina.Conclusions:Intravitreal injection of 100μM ART could downregulate TNF-αwhile upregulate IL-10 in the mouse retina without causing retinal functional deterioration and RGC loss.ART might be used as anti-inflammatory agent for retinal disorders.展开更多
Monocyte chemoattractant protein-1(MCP-1)/CCL2 is a C–C chemokine involved in the activation and recruitment of monocytic cells to injury sites.MCP-1/CCL2 can induce either neuroprotection or neurodestruction in vitr...Monocyte chemoattractant protein-1(MCP-1)/CCL2 is a C–C chemokine involved in the activation and recruitment of monocytic cells to injury sites.MCP-1/CCL2 can induce either neuroprotection or neurodestruction in vitro,depending on the experimental model.We aim to use MCP-1/CCL2 as an experimental tool to investigate the morphological changes of microglia when loss of healthy retinal ganglion cells(RGCs)is exacerbated or attenuated in an experimental glaucoma model.While a high concentration(1000 ng)of MCP-1/CCL2 and lipopolysaccharide(LPS)-exacerbated RGC loss,100 ng MCP-1/CCL2 provided neuroprotection towards RGC.Neuroprotective MCP-1/CCL2(100 ng)also upregulated insulin-like growth factor-1(IGF-1)immunoreactivity in the RGCs.The neuroprotective effect of MCP-1/CCL2 was not due to the massiveinfiltration of microglia/macrophages.Taken together,this is the first report showing that an appropriate amount of MCP-1/CCL2 can protect RGCs in experimental glaucoma.展开更多
Conflicting findings exist regarding the link between functional recovery and the regrowth of spinal tracts across the lesion leading to the restoration of functional contacts. In the present study, we investigated wh...Conflicting findings exist regarding the link between functional recovery and the regrowth of spinal tracts across the lesion leading to the restoration of functional contacts. In the present study, we investigated whether functional locomotor recovery was attributable to anatomical regeneration at postnatal day 1 (PN1), PN7, PN14 and in adult rats two months after transection injury at the tenth thoracic segment of the spinal cord. The Basso, Beattie, and Bresnahan scores showed that transection led to a failure of hindlimb locomotor function in PN14 and adult rats. However, PN1 and PN7 rats showed a significant level of stepping function after complete spinal cord transection. Unexpectedly, unlike the transected PN14 and adult rats in which the spinal cord underwent limited secondary degeneration and showed a scar at the lesion site, the rats transected at PN1 and PN7 showed massive secondary degeneration both anterograde and retrograde, leaving a >5-mm gap between the two stumps. Furthermore, retrograde tracing with fluorogold (FG) also showed that FG did not cross the transection site in PN1 and PN7 rats as in PN14 and adult rats, and re-transection of the cord caused no apparent loss in locomotor performance in the rats transected at PN1. Thus, these three lines of evidence strongly indicated that the functional recovery after transection in neonatal rats is independent of regrowth of spinal tracts across the lesion site. Our results support the notion that the recovery of locomotor function in developing rats may be due to intrinsic adaptations in the spinal circuitry below the lesion that control hindlimb locomotor activity rather than the regrowth of spinal tracts across the lesion. The difference in secondary degeneration between neonatal and adult rats remains to be explored.展开更多
Background:In the last two decades,electrical stimulation(ES)has been tested in patients with various eye diseases and shows great treatment potential in retinitis pigmentosa and optic neuropathy.However,the clinical ...Background:In the last two decades,electrical stimulation(ES)has been tested in patients with various eye diseases and shows great treatment potential in retinitis pigmentosa and optic neuropathy.However,the clinical application of ES in ophthalmology is currently limited.On the one hand,optimization and standardization of ES protocols is still an unmet need.On the other hand,poor understanding of the underlying mechanisms has hindered clinical exploitation.Main Text:Numerous experimental studies have been conducted to identify the treatment potential of ES in eye diseases and to explore the related cellular and molecular mechanisms.In this review,we summarized the in vitro and in vivo evidence related to cellular and tissue response to ES in eye diseases.We highlighted several pathways that may be utilized by ES to impose its effects on the diseased retina.Conclusions:Therapeutic effect of ES in retinal degenerative diseases might through preventing neuronal apoptosis,promoting neuronal regeneration,increasing neurotrophic factors production in Müller cells,inhibiting microglial activation,enhancing retinal blood flow,and modulating brain plasticity.Future studies are suggested to analyse changes in specific retinal cells for optimizing the treatment parameters and choosing the best fit ES delivery method in target diseases.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81941011(to XL),31771053(to HD),31730030(to XL),31971279(to ZY),31900749(to PH),31650001(to XL),31320103903(to XL),31670988(to ZY)the Natural Science Foundation of Beijing,Nos.7222004(to HD)+1 种基金a grant from Ministry of Science and Technology of China,Nos.2017YFC1104002(to ZY),2017YFC1104001(to XL)a grant from Beihang University,No.JKF-YG-22-B001(to FH)。
文摘Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.
基金supported by the Azalea (1972) Education fund to KFSo and RCCCFundamental Research Fund for The Centre Universities,No.21609101
文摘Lycium barbarum, a traditional Chinese anti-aging herb, has been shown to protect retinal ganglion cells (RGCs) in a rat chronic ocular hypertension (COH) model. Here, we investigated the expression of endothelin-1 (ET-1), a strong vasoconstrictor, and its receptors, ETA and ETB, in the COH model and assessed the effects of Lycium barbarum on the ET-1 axis. Elevated intraocular pressure (IOP) was induced in the right eye of SD rats using argon laser photocoagulation. (1) The expression of ET-1, ETA and ETB in normal and COH retinas was studied. (2) Some COH rats were fed daily with Lycium barbarum Polysaccharides (LBP) using 1 mg/kg or phosphate-buffered saline (PBS) for 3 weeks (started 1 week before photocoagulation). The effects of LBP on the expression of ET-1 and its receptors, ETA and ETB, in COH retina were evaluated. A semi-quantitative analysis of staining intensity was used to evaluate the expression levels of ET-1, ETA and ETB in retinal vasculature. We found that (1) Under COH condition, the immunoreactivity of ET-1 was increased in retina associated with an increase of ETB receptor immunoreactivity and a decrease of ETA receptor immunoreactivity. (2) After feeding COH rats with LBP, the expression of ET-1 was decreased with an increase of ETA expression and a decrease of ETB expression in the retina, especially in RGCs. (3) By comparing the staining intensity in the vasculature of COH retina in LBP-fed group with PBS-fed group, there was a decrease in the expression of ET-1 and ETA and an increase in ETB. In summary, ET-1 expression was up-regulated in the retina in COH model. LBP could decrease the expression of ET-1 and modulate the expression of its receptors, ETA and ETB, under the condition of COH. The neuroprotective effect of LBP on RGCs might be related to its ability to regulate the ET-1-mediated biological effects on RGCs and retinal vasculature.
基金supported by the Natural Science Foundation of Beijing of China,No.7192235(to LKX)
文摘Artemisinin,also called qinghaosu,is originally derived from the sweet wormwood plant(Artemisia annua),which is used in traditional Chinese medicine.Artemisinin and its derivatives(artemisinins)have been widely used for many years as anti-malarial agents,with few adverse side effects.Interestingly,evidence has recently shown that artemisinins might have a therapeutic value for several other diseases beyond malaria,including cancers,inflammatory diseases,and autoimmune disorders.Neurodegeneration is a challenging age-associated neurological disorder characterized by deterioration of neuronal structures as well as functions,whereas neuroinflammation has been considered to be an underlying factor in the development of various neurodegenerative disorders,including Alzheimer’s disease.Recently discovered properties of artemisinins suggested that they might be used to treat neurodegenerative disorders by decreasing oxidation,inflammation,and amyloid beta protein(Aβ).In this review,we will introduce artemisinins and highlight the possible mechanisms of their neuroprotective activities,suggesting that artemisinins might have therapeutic potential in neurodegenerative disorders.
基金supported by Midstream Research Program for UniversitiesHong Kong Special Administrative Region,China,No.MRP-092-17X。
文摘Lycium barbarum(LB)is a traditional Chinese medicine that has been demonstrated to exhibit a wide variety of biological functions,such as antioxidation,neuroprotection,and immune modulation.One of the main mechanisms of Alzheimer’s disease is that microglia activated by amyloid beta(Aβ)transform from the resting state to an M1 state and release pro-inflammatory cytokines to the surrounding environment.In the present study,immortalized microglial cells were pretreated with L.barbarum extract for 1 hour and then treated with oligomeric Aβfor 23 hours.The results showed that LB extract significantly increased the survival of oligomeric Aβ-induced microglial cells,downregulated the expression of M1 pro-inflammatory markers(inducible nitric oxide synthase,tumor necrosis factorα,interleukin-6,and interleukin-1β),and upregulated the expression of M2 anti-inflammatory markers(arginase-1,chitinase-like protein 3,and interleukin-4).LB extract also inhibited the oligomeric Aβ-induced secretion of tumor necrosis factorα,interleukin-6,and interleukin-1βin microglial cells.The results of in vitro cytological experiments suggest that,in microglial cells,LB extract can inhibit oligomeric Aβ-induced M1 polarization and concomitant inflammatory reactions,and promote M2 polarization.
基金supported by Midstream Research Programme for Universities,Hong Kong to Kin Chiu(Project No:MRP-092–17X).
文摘Background:Artesunate(ART),a member of the artemisinin family,possesses multi-properties,including antiinflammation,anti-oxidation,and anti-tumor.ART was recently reported to show anti-neovascularization effect on the cornea,iris,and retina.Compared to the expensive anti-VEGF treatment,this versatile,economical treatment option is attractive in the ophthalmic field.The safety and toxicity profile of ART intravitreal application are in utmost need.Methods:In this study,immortalized microglial(IMG)cells were treated with ART to determine the safe concentrations without inducing overt inflammatory reactions.Reverse transcription-polymerase chain reaction analysis was used to detect the cytokine expressions in IMG cells in response to ART stimulation.Various doses of ART were intravitreally injected into the right eyes of C57BL/6 mice.Retinal function was tested by electroretinogram,and retinal ganglion cell(RGC)survival was evaluated by counting Brn3a stained cells in flat-mounted retinas at 7 days after ART injection.Results:ART below 5μM was safe for IMG cells in vitro.Both 2.5 and 5μM ART treatment increased IL-10 gene expression in IMG cells while not changing IL-1β,IL-6,TNF-α,and Arg-1.In the in vivo study,intravitreal injection of ART below 100μM did not cause deterioration in the retinal function and RGC survival of the mouse eyes,while 1 mM ART treatment significantly attenuated both the scotopic and photopic b-wave amplitudes and impaired RGC survival.In addition,treatment with ART of 25,50,and 100μM significantly decreased TNF-αgene expression while ART of 100μM significantly increased IL-10 in the mouse retina.Conclusions:Intravitreal injection of 100μM ART could downregulate TNF-αwhile upregulate IL-10 in the mouse retina without causing retinal functional deterioration and RGC loss.ART might be used as anti-inflammatory agent for retinal disorders.
基金This work was supported by the Glaucoma Foundation,New York,USA.Kin Chiu is supported by a postdoctoral fellowship from the University of HongKong.
文摘Monocyte chemoattractant protein-1(MCP-1)/CCL2 is a C–C chemokine involved in the activation and recruitment of monocytic cells to injury sites.MCP-1/CCL2 can induce either neuroprotection or neurodestruction in vitro,depending on the experimental model.We aim to use MCP-1/CCL2 as an experimental tool to investigate the morphological changes of microglia when loss of healthy retinal ganglion cells(RGCs)is exacerbated or attenuated in an experimental glaucoma model.While a high concentration(1000 ng)of MCP-1/CCL2 and lipopolysaccharide(LPS)-exacerbated RGC loss,100 ng MCP-1/CCL2 provided neuroprotection towards RGC.Neuroprotective MCP-1/CCL2(100 ng)also upregulated insulin-like growth factor-1(IGF-1)immunoreactivity in the RGCs.The neuroprotective effect of MCP-1/CCL2 was not due to the massiveinfiltration of microglia/macrophages.Taken together,this is the first report showing that an appropriate amount of MCP-1/CCL2 can protect RGCs in experimental glaucoma.
基金Acknowledgements The work done by this laboratory has been or is currently supported by The Glaucoma Foundation, USA American Health Assistant Foundation, USA+5 种基金 HKU Alzheimer＇s Disease Research Network under Strategic Theme Research on Healthy Aging University Strategic Research Theme on Drug Discovery Research Fund for the Control of Infectious Diseases （09080822） from Food and Health Bureau of Hong Kong SAR Government General Research Fund （761609M ＆ 755206M） from Research Grant Council National Science Foundation of China - Research Grant Council of Hong Kong Joint Research Scheme （N_HKU 707/07M） and HKU Seed Funding for Basic Research （200811159082）.
基金supported by the Hong Kong SCI Fundthe National Basic Research Development Program (973 program) of China (2011CB504402)
文摘Conflicting findings exist regarding the link between functional recovery and the regrowth of spinal tracts across the lesion leading to the restoration of functional contacts. In the present study, we investigated whether functional locomotor recovery was attributable to anatomical regeneration at postnatal day 1 (PN1), PN7, PN14 and in adult rats two months after transection injury at the tenth thoracic segment of the spinal cord. The Basso, Beattie, and Bresnahan scores showed that transection led to a failure of hindlimb locomotor function in PN14 and adult rats. However, PN1 and PN7 rats showed a significant level of stepping function after complete spinal cord transection. Unexpectedly, unlike the transected PN14 and adult rats in which the spinal cord underwent limited secondary degeneration and showed a scar at the lesion site, the rats transected at PN1 and PN7 showed massive secondary degeneration both anterograde and retrograde, leaving a >5-mm gap between the two stumps. Furthermore, retrograde tracing with fluorogold (FG) also showed that FG did not cross the transection site in PN1 and PN7 rats as in PN14 and adult rats, and re-transection of the cord caused no apparent loss in locomotor performance in the rats transected at PN1. Thus, these three lines of evidence strongly indicated that the functional recovery after transection in neonatal rats is independent of regrowth of spinal tracts across the lesion site. Our results support the notion that the recovery of locomotor function in developing rats may be due to intrinsic adaptations in the spinal circuitry below the lesion that control hindlimb locomotor activity rather than the regrowth of spinal tracts across the lesion. The difference in secondary degeneration between neonatal and adult rats remains to be explored.
文摘Background:In the last two decades,electrical stimulation(ES)has been tested in patients with various eye diseases and shows great treatment potential in retinitis pigmentosa and optic neuropathy.However,the clinical application of ES in ophthalmology is currently limited.On the one hand,optimization and standardization of ES protocols is still an unmet need.On the other hand,poor understanding of the underlying mechanisms has hindered clinical exploitation.Main Text:Numerous experimental studies have been conducted to identify the treatment potential of ES in eye diseases and to explore the related cellular and molecular mechanisms.In this review,we summarized the in vitro and in vivo evidence related to cellular and tissue response to ES in eye diseases.We highlighted several pathways that may be utilized by ES to impose its effects on the diseased retina.Conclusions:Therapeutic effect of ES in retinal degenerative diseases might through preventing neuronal apoptosis,promoting neuronal regeneration,increasing neurotrophic factors production in Müller cells,inhibiting microglial activation,enhancing retinal blood flow,and modulating brain plasticity.Future studies are suggested to analyse changes in specific retinal cells for optimizing the treatment parameters and choosing the best fit ES delivery method in target diseases.
