Spinal cord injuries have overwhelming physical and occupational implications for patients.Moreover,the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and...Spinal cord injuries have overwhelming physical and occupational implications for patients.Moreover,the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and resources,adding a substantial burden to the healthcare system and patients'families.In this context,chondroitinase ABC,a bacterial enzyme isolated from Proteus vulgaris that is modified to facilitate expression and secretion in mammals,has emerged as a promising therapeutic agent.It works by degrading chondroitin sulfate proteoglycans,cleaving the glycosaminoglycanchains of chondroitin sulfate proteoglycans into soluble disaccharides or tetrasaccharides.Chondroitin sulfate proteoglycans are potent axon growth inhibitors and principal constituents of the extracellular matrix surrounding glial and neuronal cells attached to glycosaminoglycan chains.Chondroitinase ABC has been shown to play an effective role in promoting recovery from acute and chronic spinal cord injury by improving axonal regeneration and sprouting,enhancing the plasticity of perineuronal nets,inhibiting neuronal apoptosis,and modulating immune responses in various animal models.In this review,we introduce the classification and pathological mechanisms of spinal cord injury and discuss the pathophysiological role of chondroitin sulfate proteoglycans in spinal cord injury.We also highlight research advancements in spinal cord injury treatment strategies,with a focus on chondroitinase ABC,and illustrate how improvements in chondroitinase ABC stability,enzymatic activity,and delivery methods have enhanced injured spinal cord repair.Furthermore,we emphasize that combination treatment with chondroitinase ABC further enhances therapeutic efficacy.This review aimed to provide a comprehensive understanding of the current trends and future directions of chondroitinase ABC-based spinal cord injury therapies,with an emphasis on how modern technologies are accelerating the optimization of chondroitinase ABC development.展开更多
A significant number of anticancer drugs fail to treat primary and metastatic brain tumors primarily because of the complex blood-brain barrier(BBB)and overexpression of ATP-binding cassette(ABC)transporters,which dec...A significant number of anticancer drugs fail to treat primary and metastatic brain tumors primarily because of the complex blood-brain barrier(BBB)and overexpression of ATP-binding cassette(ABC)transporters,which decrease drug penetration into the central nervous system and ultimately into tumors.It is noteworthy that the ABC transporters,ABCB1[known as P-glycoprotein(P-gp)]and ABCG2[known as breast cancer resistance protein(BCRP)],are overexpressed in brain tumors,including common gliomas.The co-presence of these transporters may negate the inhibition of either transporter,particularly if both transport the same anticancer drug.The cellular export of drugs by ABC transporters has been implicated in mediating resistance to anticancer drugs.However,the clinical relevance as a therapeutic target in human tumors remains a matter of contention.Although effective and clinically approved ABC transporter inhibitors could potentially overcome drug resistance,none are currently approved.Furthermore,the ABC transporter inhibitors in clinical trials produced low or no clinical efficacy,significant toxicities,and unsuitable pharmacokinetic profiles.Therefore,innovative approaches are needed to efficaciously and simultaneously inhibit these transporters to surmount anticancer drug resistance.This review emphasizes the clinical significance of ABC transporters in diminishing the efficacy of brain tumor treatments.The molecular alterations in BBB following brain tumor development,which are linked to various cancer therapies,are discussed.The overexpression of ABCB1 and ABCG2 at the BBB is discussed,potential strategies to decrease the export of chemotherapeutics by these transporters and the associated challenges and failures are discussed,and the implementation of novel approaches is considered.展开更多
Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration...Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.展开更多
基金supported by the National Natural Science Foundation of China,No.82002645China Postdoctoral Science Foundation,No.2022M722321Jiangsu Funding Program for Excellent Postdoctoral Talent,No.2022ZB552(all to YH)。
文摘Spinal cord injuries have overwhelming physical and occupational implications for patients.Moreover,the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and resources,adding a substantial burden to the healthcare system and patients'families.In this context,chondroitinase ABC,a bacterial enzyme isolated from Proteus vulgaris that is modified to facilitate expression and secretion in mammals,has emerged as a promising therapeutic agent.It works by degrading chondroitin sulfate proteoglycans,cleaving the glycosaminoglycanchains of chondroitin sulfate proteoglycans into soluble disaccharides or tetrasaccharides.Chondroitin sulfate proteoglycans are potent axon growth inhibitors and principal constituents of the extracellular matrix surrounding glial and neuronal cells attached to glycosaminoglycan chains.Chondroitinase ABC has been shown to play an effective role in promoting recovery from acute and chronic spinal cord injury by improving axonal regeneration and sprouting,enhancing the plasticity of perineuronal nets,inhibiting neuronal apoptosis,and modulating immune responses in various animal models.In this review,we introduce the classification and pathological mechanisms of spinal cord injury and discuss the pathophysiological role of chondroitin sulfate proteoglycans in spinal cord injury.We also highlight research advancements in spinal cord injury treatment strategies,with a focus on chondroitinase ABC,and illustrate how improvements in chondroitinase ABC stability,enzymatic activity,and delivery methods have enhanced injured spinal cord repair.Furthermore,we emphasize that combination treatment with chondroitinase ABC further enhances therapeutic efficacy.This review aimed to provide a comprehensive understanding of the current trends and future directions of chondroitinase ABC-based spinal cord injury therapies,with an emphasis on how modern technologies are accelerating the optimization of chondroitinase ABC development.
基金supported by Arkansas Bioscience Institute funds (ABI-GR020025) from University of Arkansas for Medical Sciences
文摘A significant number of anticancer drugs fail to treat primary and metastatic brain tumors primarily because of the complex blood-brain barrier(BBB)and overexpression of ATP-binding cassette(ABC)transporters,which decrease drug penetration into the central nervous system and ultimately into tumors.It is noteworthy that the ABC transporters,ABCB1[known as P-glycoprotein(P-gp)]and ABCG2[known as breast cancer resistance protein(BCRP)],are overexpressed in brain tumors,including common gliomas.The co-presence of these transporters may negate the inhibition of either transporter,particularly if both transport the same anticancer drug.The cellular export of drugs by ABC transporters has been implicated in mediating resistance to anticancer drugs.However,the clinical relevance as a therapeutic target in human tumors remains a matter of contention.Although effective and clinically approved ABC transporter inhibitors could potentially overcome drug resistance,none are currently approved.Furthermore,the ABC transporter inhibitors in clinical trials produced low or no clinical efficacy,significant toxicities,and unsuitable pharmacokinetic profiles.Therefore,innovative approaches are needed to efficaciously and simultaneously inhibit these transporters to surmount anticancer drug resistance.This review emphasizes the clinical significance of ABC transporters in diminishing the efficacy of brain tumor treatments.The molecular alterations in BBB following brain tumor development,which are linked to various cancer therapies,are discussed.The overexpression of ABCB1 and ABCG2 at the BBB is discussed,potential strategies to decrease the export of chemotherapeutics by these transporters and the associated challenges and failures are discussed,and the implementation of novel approaches is considered.
基金supported in part by NIH R01 NS100531,R01 NS103481NIH R21NS130241(to LD)+3 种基金Merit Review Award I01 BX002356,I01 BX003705 from the U.S.Department of Veterans AffairsIndiana Spinal Cord and Brain Injury Research Foundation(No.19919)Mari Hulman George Endowment Funds(to XMX)Indiana Spinal Cord&Brain Injury Research Fund from ISDH(to NKL and LD)。
文摘Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.
