Spinal cord injury （SCI） can have a range of debilitating effects and permanently alter the capabilities and quality of life of survivors. The first specialized centers of care for SCI were established in 1944 and s...Spinal cord injury （SCI） can have a range of debilitating effects and permanently alter the capabilities and quality of life of survivors. The first specialized centers of care for SCI were established in 1944 and since then an increasing amount of research has been carried out in this area. Despite this, the present treatment and care levels for SCI are not comparable to those in other areas of medicine. In the clinic, the aim of SCI treatment is primarily to limit secondary damage by reducing compression in trauma spots and stabilizing the spinal column. Currently, no effective strategy for functional recovery is offered. In this review, we focus on research progress on the molecular mechanisms underlying SCI, and assess the treatment outcomes of SCI in animal models, i.e., neurotrophins and stem cells are discussed as pre-clinical therapies in animal models. We also assess the resources available and national research projects carried out on SCI in China in recent years, as well as making recommendations for the future allocation of funds in this area.展开更多
Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has ev...Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease,owing to its rapid advancement over the recent decade.Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets,including those that were once considered undruggable.However,lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application,necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the bloodbrain barrier.Nanotechnology has emerged as a possible solution,and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery.By reducing the enzymatic breakdown of genetic components,nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy.Liposomes,polymeric nanoparticles,magnetic nanoparticles,dendrimers,and micelles are examples of nanocarriers that have been designed,and each has its own set of features.Furthermore,recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities.In this paper,we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease.展开更多
Adult neurogenesis involves persistent proliferative neuroprogenitor populations that reside within distinct regions of the brain.This phenomenon was first described over 50 years ago and it is now firmly established ...Adult neurogenesis involves persistent proliferative neuroprogenitor populations that reside within distinct regions of the brain.This phenomenon was first described over 50 years ago and it is now firmly established that new neurons are continually generated in distinct regions of the adult brain.The potential of enhancing the neurogenic process lies in improved brain cognition and neuronal plasticity particularly in the context of neuronal injury and neurodegenerative disorders.In addition,adult neurogenesis might also play a role in mood and affective disorders.The factors that regulate adult neurogenesis have been broadly studied.However,the underlying molecular mechanisms of regulating neurogenesis are still not fully defined.In this review,we will provide critical analysis of our current understanding of the factors and molecular mechanisms that determine neurogenesis.We will further discuss pre-clinical and clinical studies that have investigated the potential of modulating neurogenesis as therapeutic intervention in neurodegeneration.展开更多
Several mammalian animal models of traumatic brain injury have been used, mostly rodents. However, reparative mechanisms in mammalian brain are very limited, and newly formed neurons do not survive for long time. The ...Several mammalian animal models of traumatic brain injury have been used, mostly rodents. However, reparative mechanisms in mammalian brain are very limited, and newly formed neurons do not survive for long time. The brain of adult zebrafish, a teleost fish widely used as vertebrate model, possesses high regenerative properties after injury due to the presence of numerous stem cells niches. The ventricular lining of the zebrafish dorsal telencephalon is the most studied neuronal stem cell niche because its dorso-lateral zone is considered the equivalent to the hippocampus of mammals which contains one of the two constitutive neurogenic niches of mammals. To mimic TBI, stab wound in the dorso-lateral telencephalon of zebrafish was used in studies devoted to fish regenerative properties. Brain-derived neurotrophic factor, which is known to play key roles in the repair process after traumatic brain lesions, persists around the lesioned area of injured telencephalon of adult zebrafish. These results are extensively compared to reparative processes in rodent brain. Considering the complete repair of the damaged area in fish, it could be tempting to consider brain-derived neurotrophic factor as a factor contributing to create a permissive environment that enables the establishment of new neuronal population in damaged brain.展开更多
It has long been known that the brain is an immunologically privileged site in normal conditions. Although the cascade of immune responses can occur as long as there is a neuronal injury or a potent immune stimulation...It has long been known that the brain is an immunologically privileged site in normal conditions. Although the cascade of immune responses can occur as long as there is a neuronal injury or a potent immune stimulation, how the brain keeps glial cells in a quiescent state is still unclear. Increasing efforts have been made by several laboratories to elucidate how repression oi~ immune responses is achieved in the neuronal environment. The suppression factors include neurotransmitters, neurohormones, neurotrophic factors, anti-inflammatory factors, and cell-cell contact via adhesion molecules or CD200 receptor. This review discusses how these factors affect the cascade of cerebral immune responses because no single factor listed above can fully account for the immune suppression. While several factors contribute to the suppression of immune responses, activation of glial cells and their production of pro-inflammatory factors do occur as long as there is a neuronal injury, suggesting that some neuronal components facilitate immune responses. This review also discusses which signals initiate or augment cerebral immune responses so that stimulatory signals override the suppressive signals. Increasing lines of evidence have demonstrated that immune responses in the brain are not always detrimental to neurons. Attempt to simply clear off inflammatory factors in the CNS may not be appropriate for neurons in neurological disorders. Appropriate control of immune cells in the CNS may be beneficial to neurons or even neuroregeneration. Therefore, understanding the mechanisms underlying immune suppression may help us to reshape pharmacological interventions against inflammation in many neurological disorders.展开更多
Advances in the neurobiology of growth factors, neural development, and prevention of cell death have resulted in a heightened clinical interest for the development of protective and regenerative neuromodulatory strat...Advances in the neurobiology of growth factors, neural development, and prevention of cell death have resulted in a heightened clinical interest for the development of protective and regenerative neuromodulatory strategies for the cavernous nerves （CNs）, as therapies for prostate cancer and other pelvic malignancies often result in neuronal damage and debilitating loss of sexual function. Nitric oxide released from the axonal end plates of these nerves within the corpora cavernosa causes relaxation of smooth muscle, initiating the haemodynamic changes of penile erection as well as contributing to maintained tumescence; the loss of CN function is primarily responsible for the development of erectile dysfunction （ED） after pelvic surgery and serves as the primary target for potential neuroprotective or regenerative strategies. Evidence from pre-clinical studies for select neuromodulatory approaches is reviewed, including neurotrophins, glial cell line-derived neurotrophic factors （GDNF）, bone morphogenic proteins, immunophilin ligands, erythropoetin （EPO）, and stem cells.展开更多
Aging is a global phenomenon and a complex biological process of all living beings that introduces various changes.During this physiological process,the brain is the most affected organ due to changes in its structura...Aging is a global phenomenon and a complex biological process of all living beings that introduces various changes.During this physiological process,the brain is the most affected organ due to changes in its structural and chemical functions,such as changes in plasticity and decrease in the number,diameter,length,and branching of dendrites and dendritic spines.Likewise,it presents a great reduction in volume resulting from the contraction of the gray matter.Consequently,aging can affect not only cognitive functions,including learning and memory,but also the quality of life of older people.As a result of the phenomena,various molecules with notable neuroprotective capacity have been proposed,which provide a therapeutic alternative for people under conditions of aging or some neurodegenerative diseases.It is important to indicate that in recent years the use of molecules with neurotrophic activity has shown interesting results when evaluated in in vivo models.This review aims to describe the neurotrophic potential of molecules such as resveratrol(3,5,4′-trihydroxystilbene),neurotrophins(brain-derived neurotrophic factor),and neurotrophic-type compounds such as the terminal carboxyl domain of the heavy chain of tetanus toxin,cerebrolysin,neuropeptide-12,and rapamycin.Most of these molecules have been evaluated by our research group.Studies suggest that these molecules exert an important therapeutic potential,restoring brain function in aging conditions or models of neurodegenerative diseases.Hence,our interest is in describing the current scientific evidence that supports the therapeutic potential of these molecules with active neurotrophic.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells.Recent works have revealed that the dy...Pancreatic ductal adenocarcinoma(PDAC)is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells.Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion(PNI),a clinical pathological feature of PDAC.The formation and function of PNI are dually regulated by molecular(e.g.,involving neurotrophins,cytokines,chemokines,and neurotransmitters),metabolic(e.g.,serine metabolism),and cellular mechanisms(e.g.,involving Schwann cells,stromal cells,T cells,and macrophages).Such integrated mechanisms of PNI not only support tumor development,growth,invasion,and metastasis but also mediate the formation of pain,all of which are closely related to poor disease prognosis in PDAC.This review details the modulation,signaling pathways,detection,and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.展开更多
Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline.This process represents the major risk factor for aging-related diseases such as Alz...Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline.This process represents the major risk factor for aging-related diseases such as Alzheimer’s disease,Parkinson’s disease,and ischemic stroke.The incidence of all these pathologies increases exponentially with age.Research on aging biology has currently focused on elucidating molecular mechanisms leading to the development of those pathologies.Cognitive deficit and neurodegeneration,common features of aging-related pathologies,are related to the alteration of the activity and levels of neurotrophic factors,such as brain-derived neurotrophic factor,nerve growth factor,and glial cell-derived neurotrophic factor.For this reason,treatments that modulate neurotrophin levels have acquired a great deal of interest in preventing neurodegeneration and promoting neural regeneration in several neurological diseases.Those treatments include both the direct administration of neurotrophic factors and the induced expression with viral vectors,neurotrophins’binding with biomaterials or other molecules to increase their bioavailability but also cell-based therapies.Considering neurotrophins’crucial role in aging pathologies,here we discuss the involvement of several neurotrophic factors in the most common brain aging-related diseases and the most recent therapeutic approaches that provide direct and sustained neurotrophic support.展开更多
Purpose： The relationship between acute exercise and executive functions in college students with attention deficit hyperactivity disorder （ADHD） has not been clearly established. The purpose of this preliminary st...Purpose： The relationship between acute exercise and executive functions in college students with attention deficit hyperactivity disorder （ADHD） has not been clearly established. The purpose of this preliminary study was to examine the difference in cognitive performance between college students with and without ADHD and to explore the effects of acute exercise on multiple aspects of executive functions and on serum brain derived neurotrophic factor （BDNF）. Methods： College students （normal： n = 10; ADHD： n = 10） performed the Stroop Test, Trail Making Test, and Digit Span Test prior to and after an acute exercise intervention. Blood samples were obtained prior to the pre-test cognitive test performance and then again after exercise and prior to the post-test cognitive test performance. Results： Students with ADHD exhibited impaired executive functions, particularly on inhibition. Additionally, while acute exercise improved all aspects of executive functions in those without ADHD, acute exercise only improved inhibitory performance for those with ADHD. Further, BDNF was not influenced by acute exercise regardless of the subjects＇ ADHD status. Conclusion： These results provide preliminary evidence for exercise as a potential adjunct treatment for benefitting inhibition in college students with ADHD.展开更多
文摘Spinal cord injury （SCI） can have a range of debilitating effects and permanently alter the capabilities and quality of life of survivors. The first specialized centers of care for SCI were established in 1944 and since then an increasing amount of research has been carried out in this area. Despite this, the present treatment and care levels for SCI are not comparable to those in other areas of medicine. In the clinic, the aim of SCI treatment is primarily to limit secondary damage by reducing compression in trauma spots and stabilizing the spinal column. Currently, no effective strategy for functional recovery is offered. In this review, we focus on research progress on the molecular mechanisms underlying SCI, and assess the treatment outcomes of SCI in animal models, i.e., neurotrophins and stem cells are discussed as pre-clinical therapies in animal models. We also assess the resources available and national research projects carried out on SCI in China in recent years, as well as making recommendations for the future allocation of funds in this area.
基金supported by the Intramural Research Program National Institute on Aginq,NIH。
文摘Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease,owing to its rapid advancement over the recent decade.Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets,including those that were once considered undruggable.However,lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application,necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the bloodbrain barrier.Nanotechnology has emerged as a possible solution,and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery.By reducing the enzymatic breakdown of genetic components,nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy.Liposomes,polymeric nanoparticles,magnetic nanoparticles,dendrimers,and micelles are examples of nanocarriers that have been designed,and each has its own set of features.Furthermore,recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities.In this paper,we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease.
基金DN is a recipient of an ARC Future Fellowship(FT120100193)a Cancer Council Queensland Grant-in-Aid(1101931).
文摘Adult neurogenesis involves persistent proliferative neuroprogenitor populations that reside within distinct regions of the brain.This phenomenon was first described over 50 years ago and it is now firmly established that new neurons are continually generated in distinct regions of the adult brain.The potential of enhancing the neurogenic process lies in improved brain cognition and neuronal plasticity particularly in the context of neuronal injury and neurodegenerative disorders.In addition,adult neurogenesis might also play a role in mood and affective disorders.The factors that regulate adult neurogenesis have been broadly studied.However,the underlying molecular mechanisms of regulating neurogenesis are still not fully defined.In this review,we will provide critical analysis of our current understanding of the factors and molecular mechanisms that determine neurogenesis.We will further discuss pre-clinical and clinical studies that have investigated the potential of modulating neurogenesis as therapeutic intervention in neurodegeneration.
文摘Several mammalian animal models of traumatic brain injury have been used, mostly rodents. However, reparative mechanisms in mammalian brain are very limited, and newly formed neurons do not survive for long time. The brain of adult zebrafish, a teleost fish widely used as vertebrate model, possesses high regenerative properties after injury due to the presence of numerous stem cells niches. The ventricular lining of the zebrafish dorsal telencephalon is the most studied neuronal stem cell niche because its dorso-lateral zone is considered the equivalent to the hippocampus of mammals which contains one of the two constitutive neurogenic niches of mammals. To mimic TBI, stab wound in the dorso-lateral telencephalon of zebrafish was used in studies devoted to fish regenerative properties. Brain-derived neurotrophic factor, which is known to play key roles in the repair process after traumatic brain lesions, persists around the lesioned area of injured telencephalon of adult zebrafish. These results are extensively compared to reparative processes in rodent brain. Considering the complete repair of the damaged area in fish, it could be tempting to consider brain-derived neurotrophic factor as a factor contributing to create a permissive environment that enables the establishment of new neuronal population in damaged brain.
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）.
文摘It has long been known that the brain is an immunologically privileged site in normal conditions. Although the cascade of immune responses can occur as long as there is a neuronal injury or a potent immune stimulation, how the brain keeps glial cells in a quiescent state is still unclear. Increasing efforts have been made by several laboratories to elucidate how repression oi~ immune responses is achieved in the neuronal environment. The suppression factors include neurotransmitters, neurohormones, neurotrophic factors, anti-inflammatory factors, and cell-cell contact via adhesion molecules or CD200 receptor. This review discusses how these factors affect the cascade of cerebral immune responses because no single factor listed above can fully account for the immune suppression. While several factors contribute to the suppression of immune responses, activation of glial cells and their production of pro-inflammatory factors do occur as long as there is a neuronal injury, suggesting that some neuronal components facilitate immune responses. This review also discusses which signals initiate or augment cerebral immune responses so that stimulatory signals override the suppressive signals. Increasing lines of evidence have demonstrated that immune responses in the brain are not always detrimental to neurons. Attempt to simply clear off inflammatory factors in the CNS may not be appropriate for neurons in neurological disorders. Appropriate control of immune cells in the CNS may be beneficial to neurons or even neuroregeneration. Therefore, understanding the mechanisms underlying immune suppression may help us to reshape pharmacological interventions against inflammation in many neurological disorders.
文摘Advances in the neurobiology of growth factors, neural development, and prevention of cell death have resulted in a heightened clinical interest for the development of protective and regenerative neuromodulatory strategies for the cavernous nerves （CNs）, as therapies for prostate cancer and other pelvic malignancies often result in neuronal damage and debilitating loss of sexual function. Nitric oxide released from the axonal end plates of these nerves within the corpora cavernosa causes relaxation of smooth muscle, initiating the haemodynamic changes of penile erection as well as contributing to maintained tumescence; the loss of CN function is primarily responsible for the development of erectile dysfunction （ED） after pelvic surgery and serves as the primary target for potential neuroprotective or regenerative strategies. Evidence from pre-clinical studies for select neuromodulatory approaches is reviewed, including neurotrophins, glial cell line-derived neurotrophic factors （GDNF）, bone morphogenic proteins, immunophilin ligands, erythropoetin （EPO）, and stem cells.
文摘Aging is a global phenomenon and a complex biological process of all living beings that introduces various changes.During this physiological process,the brain is the most affected organ due to changes in its structural and chemical functions,such as changes in plasticity and decrease in the number,diameter,length,and branching of dendrites and dendritic spines.Likewise,it presents a great reduction in volume resulting from the contraction of the gray matter.Consequently,aging can affect not only cognitive functions,including learning and memory,but also the quality of life of older people.As a result of the phenomena,various molecules with notable neuroprotective capacity have been proposed,which provide a therapeutic alternative for people under conditions of aging or some neurodegenerative diseases.It is important to indicate that in recent years the use of molecules with neurotrophic activity has shown interesting results when evaluated in in vivo models.This review aims to describe the neurotrophic potential of molecules such as resveratrol(3,5,4′-trihydroxystilbene),neurotrophins(brain-derived neurotrophic factor),and neurotrophic-type compounds such as the terminal carboxyl domain of the heavy chain of tetanus toxin,cerebrolysin,neuropeptide-12,and rapamycin.Most of these molecules have been evaluated by our research group.Studies suggest that these molecules exert an important therapeutic potential,restoring brain function in aging conditions or models of neurodegenerative diseases.Hence,our interest is in describing the current scientific evidence that supports the therapeutic potential of these molecules with active neurotrophic.
文摘Pancreatic ductal adenocarcinoma(PDAC)is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells.Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion(PNI),a clinical pathological feature of PDAC.The formation and function of PNI are dually regulated by molecular(e.g.,involving neurotrophins,cytokines,chemokines,and neurotransmitters),metabolic(e.g.,serine metabolism),and cellular mechanisms(e.g.,involving Schwann cells,stromal cells,T cells,and macrophages).Such integrated mechanisms of PNI not only support tumor development,growth,invasion,and metastasis but also mediate the formation of pain,all of which are closely related to poor disease prognosis in PDAC.This review details the modulation,signaling pathways,detection,and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.
文摘Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline.This process represents the major risk factor for aging-related diseases such as Alzheimer’s disease,Parkinson’s disease,and ischemic stroke.The incidence of all these pathologies increases exponentially with age.Research on aging biology has currently focused on elucidating molecular mechanisms leading to the development of those pathologies.Cognitive deficit and neurodegeneration,common features of aging-related pathologies,are related to the alteration of the activity and levels of neurotrophic factors,such as brain-derived neurotrophic factor,nerve growth factor,and glial cell-derived neurotrophic factor.For this reason,treatments that modulate neurotrophin levels have acquired a great deal of interest in preventing neurodegeneration and promoting neural regeneration in several neurological diseases.Those treatments include both the direct administration of neurotrophic factors and the induced expression with viral vectors,neurotrophins’binding with biomaterials or other molecules to increase their bioavailability but also cell-based therapies.Considering neurotrophins’crucial role in aging pathologies,here we discuss the involvement of several neurotrophic factors in the most common brain aging-related diseases and the most recent therapeutic approaches that provide direct and sustained neurotrophic support.
文摘Purpose： The relationship between acute exercise and executive functions in college students with attention deficit hyperactivity disorder （ADHD） has not been clearly established. The purpose of this preliminary study was to examine the difference in cognitive performance between college students with and without ADHD and to explore the effects of acute exercise on multiple aspects of executive functions and on serum brain derived neurotrophic factor （BDNF）. Methods： College students （normal： n = 10; ADHD： n = 10） performed the Stroop Test, Trail Making Test, and Digit Span Test prior to and after an acute exercise intervention. Blood samples were obtained prior to the pre-test cognitive test performance and then again after exercise and prior to the post-test cognitive test performance. Results： Students with ADHD exhibited impaired executive functions, particularly on inhibition. Additionally, while acute exercise improved all aspects of executive functions in those without ADHD, acute exercise only improved inhibitory performance for those with ADHD. Further, BDNF was not influenced by acute exercise regardless of the subjects＇ ADHD status. Conclusion： These results provide preliminary evidence for exercise as a potential adjunct treatment for benefitting inhibition in college students with ADHD.
