Parkinson's disease(PD)is a common neurodegenerative disorder that primarily affects the elderly.While the etiology of PD is likely multifactorial with the involvement of genetic,environmental,aging and other fact...Parkinson's disease(PD)is a common neurodegenerative disorder that primarily affects the elderly.While the etiology of PD is likely multifactorial with the involvement of genetic,environmental,aging and other factors,α-synuclein(α-syn)pathology is a pivotal mechanism underlying the development of PD.In recent years,astrocytes have attracted considerable attention in the field.Although astrocytes perform a variety of physiological functions in the brain,they are pivotal mediators ofα-syn toxicity since they internalizeα-syn released from damaged neurons,and this triggers an inflammatory response,protein degradation dysfunction,mitochondrial dysfunction and endoplasmic reticulum stress.Astrocytes are indispensable coordinators in the background of several genetic mutations,including PARK7,GBA1,LRRK2,ATP13A2,PINK1,PRKN and PLA2G6.As the most abundant glial cells in the brain,functional astrocytes can be replenished and even converted to functional neurons.In this review,we discuss astrocyte dysfunction in PD with an emphasis onα-syn toxicity and genetic modulation and conclude that astrocyte replenishment is a valuable therapeutic approach in PD.展开更多
A new conceptual model has been proposed for Parkinson's disease(PD)pathogenesis,which can be divided into triggering,facilitating,and aggravating processes[1].Mitochondria are believed to participate in all three...A new conceptual model has been proposed for Parkinson's disease(PD)pathogenesis,which can be divided into triggering,facilitating,and aggravating processes[1].Mitochondria are believed to participate in all three phases:pesticides(one of the definite triggers in PD pathogenesis)inhibit mitochondrial complex I(MCI).展开更多
Parkinson’s disease(PD)is recognized as the second most common neurodegenerative disorder after Alzheimer disease.Although a fascinating 200-year journey of research has revealed the multifaceted nature of PD[1,2],it...Parkinson’s disease(PD)is recognized as the second most common neurodegenerative disorder after Alzheimer disease.Although a fascinating 200-year journey of research has revealed the multifaceted nature of PD[1,2],its fundamental features are the loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc)and depletion of dopamine(DA)in the striatum.Iron accumulates in normal brains with aging.Such展开更多
The projections from hypothalamic magnocellular neuroendocrine cells(MNCs)to the posterior pituitary(PPi)are traditionally defined as the hypothalamo-neurohy-pophysial system(HNS),which releases oxytocin(OXT)and argin...The projections from hypothalamic magnocellular neuroendocrine cells(MNCs)to the posterior pituitary(PPi)are traditionally defined as the hypothalamo-neurohy-pophysial system(HNS),which releases oxytocin(OXT)and arginine vasopressin(AVP)into the blood stream to regulate peripheral function[1].Recently,accumulating evidence has confirmed that OXT and AVP are not only involved in peripheral regulation[2],but also contribute to various central actions[3,4],such as memory and social and stress-related behaviors[5].However,peripherally released OXT and AVP rarely cross the blood-brain barrier and return to the central nervous system.So,whether and how they exert central effects remain to be elucidated.It is supposed that MNCs projecting to the PPi also have collaterals projecting centrally,and these might be responsible for the central actions of OXT and AVP.But there has been no cell-type-specific dissection of the hypothalamic MNC projections,due to the limited methods and techniques for imaging and manipulation.展开更多
Misfoldedα-synuclein(α-syn)hallmarks the neuropathological characteristics of Parkinson's disease(PD)and acts as a"pathological seed"that promotes the progression of the disease[1].About 15%of PD patie...Misfoldedα-synuclein(α-syn)hallmarks the neuropathological characteristics of Parkinson's disease(PD)and acts as a"pathological seed"that promotes the progression of the disease[1].About 15%of PD patients have a family history,5%-10%have a monogenic disorder with a Mendelian pattern of inheritance[2],and>90 independent risk signals identified by genome-wide association studies(GWASs)can be used to explain the non-monogenic risk of PD[3].展开更多
Parkinson's disease (PD) is the second most common neurodegenerative disorder which mainly affects the motor system. The pathological characteristics of PD include the loss of dopaminergic neurons in the substantia...Parkinson's disease (PD) is the second most common neurodegenerative disorder which mainly affects the motor system. The pathological characteristics of PD include the loss of dopaminergic neurons in the substantia nigra region and dopamine depletion in the striatum. Dopamine functions as a neurotransmitter that is involved in motor control, executive functions, motivation, arousal, reinforcement, and reward [1]. The ongoing tonic levels of dopamine release in the dorsal striatum are thought to be important for the regulation of movement. Because of the dopamine depletion in the striatum, movement is affected in PD. The typical motor symptoms consist of poverty of movement, tremor at rest, rigidity, and postural instability. Meanwhile, pre-motor symptoms, including hyposmia, constipation, depression, and REM sleep behavior disorder, have been suggested to precede these typical motor symptoms by years [2]. It is usually proposed to alleviate these symptoms via boosting the levels of dopamine in PD. However, this may not be the case.展开更多
More and more evidence has suggested that iron deposition in the substantia nigra,which is correlated with motor and cognitive dysfunction,is an important trigger factor,potential biomarker,and therapeutic target for ...More and more evidence has suggested that iron deposition in the substantia nigra,which is correlated with motor and cognitive dysfunction,is an important trigger factor,potential biomarker,and therapeutic target for Parkinson's disease(PD)[1-3].Although the cellular mechanisms of nigral iron deposition have been well investigated,the exactly mechanisms,especially the origin of the increased nigral iron,have not been fully elucidated.展开更多
Neuroinflammation and a-synuclein (a-syn) aggregation are both neuropathological hallmarks of Parkinson’s disease (PD). Microglia are crucial participants in eliciting neuroinflammatory responses themselves, as well ...Neuroinflammation and a-synuclein (a-syn) aggregation are both neuropathological hallmarks of Parkinson’s disease (PD). Microglia are crucial participants in eliciting neuroinflammatory responses themselves, as well as modulating neurotoxic activity in astrocytes, therefore forming a pathway to neurodegeneration induced by both central and peripheral insults [1, 2].展开更多
Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression.Discs large homolog 1(Dlg1),an adaptor protein,regulates cell polar...Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression.Discs large homolog 1(Dlg1),an adaptor protein,regulates cell polarization and the function of K?channels,which are reported to regulate the activation of microglia.However,little is known about the role of Dlg1 in microglia and the maintenance of central nervous system homeostasis.In this study,we found that Dlg1 knockdown suppressed lipopolysaccharide(LPS)-induced inflammation by downregulating the activation of nuclear factor-jB signaling and the mitogen-activated protein kinase pathway in microglia.Moreover,using an inducible Dlg1 microglia-specific knockout(Dlg1flox/flox;CX3CR1CreER)mouse line,we found that microglial Dlg1 knockout reduced the activation of microglia and alleviated the LPS-induced depressionlike behavior.In summary,our results demonstrated that Dlg1 plays a critical role in microglial activation and thus provides a potential therapeutic target for the clinical treatment of depression.展开更多
Disturbances of Ca^(2+)homeostasis have been reported to be associated with the development of Parkinson's disease(PD)(Fig.1),which is characterized by the selective vulnerability of dopaminergic neurons in the su...Disturbances of Ca^(2+)homeostasis have been reported to be associated with the development of Parkinson's disease(PD)(Fig.1),which is characterized by the selective vulnerability of dopaminergic neurons in the substantia nigra pars compacta(SNpc).Different from the dopaminergic neurons in the ventral tegmental area(VTA),which mainly rely on hyperpolarization-activated cyclic nucleotide-gated/voltagegated channels for pacing and have a strong Ca^(2+)-buffering capacity.展开更多
Potassium ions(K+),the pivotal cations for membrane potential,are particularly important for maintaining the physiological function of neurons[1].When the concentration of extracellular K+([K+]o)is pathologically chan...Potassium ions(K+),the pivotal cations for membrane potential,are particularly important for maintaining the physiological function of neurons[1].When the concentration of extracellular K+([K+]o)is pathologically changed,the intrinsic neuronal excitability and synaptic transmission are also altered,which have profound implications for many neurological disorders such as epilepsy,Parkinson's disease,and emotional disorders[2-4].展开更多
Parkinson's disease(PD)is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc),accompanied by severe locomotor deficits[1].Deep brain stimulation(DBS)mainly targeting the s...Parkinson's disease(PD)is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc),accompanied by severe locomotor deficits[1].Deep brain stimulation(DBS)mainly targeting the subthalamic nucleus and the internal segment of the globus pallidus has now been clinically used to improve the motor symptoms of PD patients.However,these targets do not relieve the serious postural instability and freezing of gait.The mesencephalic locomotor region(MLR)plays a key role in controlling locomotion[2,3].展开更多
Wound healing has become one of the basic issues faced by the medical community because of the susceptibility of skin wounds to bacterial infection.As such,it is highly desired to design a nanocomposite hydrogel with ...Wound healing has become one of the basic issues faced by the medical community because of the susceptibility of skin wounds to bacterial infection.As such,it is highly desired to design a nanocomposite hydrogel with excellent antibacterial activity to achieve high wound closure effectiveness.Here,based on ultrasound-triggered piezocatalytic therapy,a multifunctional hydrogel is designed to promote bacteria-infected wound healing.Under ultrasonic vibration,the surface of barium titanate(BaTiO_(3),BT)nanoparticles embedded in the hydrogel rapidly generate reactive oxygen species(ROS)owing to the established strong built-in electric field,endowing the hydrogel with superior antibacterial efficacy.This modality shows intriguing advantages over conventional photodynamic therapy,such as prominent soft tissue penetration ability and the avoidance of serious skin phototoxicity after systemic administration of photosensitizers.Moreover,the hydrogel based on N-[tris(hydroxymethyl)methyl]acrylamide(THM),N-(3-aminopropyl)methacrylamide hydrochloride(APMH)and oxidized hyaluronic acid(OHA)exhibits outstanding self-healing and bioadhesive properties able to accelerate full-thickness skin wound healing.Notably,compared with the widely reported mussel-inspired adhesive hydrogels,OHA/THM-APMH hydrogel due to the multiple hydrogen bonds from unique tri-hydroxyl structure overcomes the shortage that catechol groups are easily oxidized,giving it long-term and repeatable adhesion performance.Importantly,this hybrid hydrogel confines BT nanoparticles to wound area and locally induced piezoelectric catalysis under ultrasound to eradicate bacteria,markedly improving the therapeutic biosafety and exhibits great potential for harmless treatment of bacteria-infected tissues.展开更多
基金supported by grants from the National Natural Science Foundation of China(31871049,31771124,32170984)Excellent Innovative Team of Shandong Province and Taishan Scholars Construction Project.
文摘Parkinson's disease(PD)is a common neurodegenerative disorder that primarily affects the elderly.While the etiology of PD is likely multifactorial with the involvement of genetic,environmental,aging and other factors,α-synuclein(α-syn)pathology is a pivotal mechanism underlying the development of PD.In recent years,astrocytes have attracted considerable attention in the field.Although astrocytes perform a variety of physiological functions in the brain,they are pivotal mediators ofα-syn toxicity since they internalizeα-syn released from damaged neurons,and this triggers an inflammatory response,protein degradation dysfunction,mitochondrial dysfunction and endoplasmic reticulum stress.Astrocytes are indispensable coordinators in the background of several genetic mutations,including PARK7,GBA1,LRRK2,ATP13A2,PINK1,PRKN and PLA2G6.As the most abundant glial cells in the brain,functional astrocytes can be replenished and even converted to functional neurons.In this review,we discuss astrocyte dysfunction in PD with an emphasis onα-syn toxicity and genetic modulation and conclude that astrocyte replenishment is a valuable therapeutic approach in PD.
基金This insight article,was,supportedby the National Natural Science Foundation of China(32170984 and 31871049)the Excellent Innovative Team of Shandong Provincethe Taishan Scholars Construction Project.
文摘A new conceptual model has been proposed for Parkinson's disease(PD)pathogenesis,which can be divided into triggering,facilitating,and aggravating processes[1].Mitochondria are believed to participate in all three phases:pesticides(one of the definite triggers in PD pathogenesis)inhibit mitochondrial complex I(MCI).
基金supported by grants from the National Natural Science Foundation of China(81430024,31771124,31571054,and 31371081)Excellent Innovative Team of Shandong Province and Taishan Scholars Construction Project
文摘Parkinson’s disease(PD)is recognized as the second most common neurodegenerative disorder after Alzheimer disease.Although a fascinating 200-year journey of research has revealed the multifaceted nature of PD[1,2],its fundamental features are the loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc)and depletion of dopamine(DA)in the striatum.Iron accumulates in normal brains with aging.Such
基金the National Natural Science Foundation of China(81830035 and 82003729).
文摘The projections from hypothalamic magnocellular neuroendocrine cells(MNCs)to the posterior pituitary(PPi)are traditionally defined as the hypothalamo-neurohy-pophysial system(HNS),which releases oxytocin(OXT)and arginine vasopressin(AVP)into the blood stream to regulate peripheral function[1].Recently,accumulating evidence has confirmed that OXT and AVP are not only involved in peripheral regulation[2],but also contribute to various central actions[3,4],such as memory and social and stress-related behaviors[5].However,peripherally released OXT and AVP rarely cross the blood-brain barrier and return to the central nervous system.So,whether and how they exert central effects remain to be elucidated.It is supposed that MNCs projecting to the PPi also have collaterals projecting centrally,and these might be responsible for the central actions of OXT and AVP.But there has been no cell-type-specific dissection of the hypothalamic MNC projections,due to the limited methods and techniques for imaging and manipulation.
基金supported by the National Natural Science Foundation of China(31871049 and 32170984).
文摘Misfoldedα-synuclein(α-syn)hallmarks the neuropathological characteristics of Parkinson's disease(PD)and acts as a"pathological seed"that promotes the progression of the disease[1].About 15%of PD patients have a family history,5%-10%have a monogenic disorder with a Mendelian pattern of inheritance[2],and>90 independent risk signals identified by genome-wide association studies(GWASs)can be used to explain the non-monogenic risk of PD[3].
基金supported by grants from the National Natural Science Foundation of China(81430024 and31771124)the China Postdoctoral Science Foundation(2017M622128)+1 种基金Qingdao Postdoctoral Research ProjectShandong Province Medical and Health Science and Technology Development Project(2017WS121)
文摘Parkinson's disease (PD) is the second most common neurodegenerative disorder which mainly affects the motor system. The pathological characteristics of PD include the loss of dopaminergic neurons in the substantia nigra region and dopamine depletion in the striatum. Dopamine functions as a neurotransmitter that is involved in motor control, executive functions, motivation, arousal, reinforcement, and reward [1]. The ongoing tonic levels of dopamine release in the dorsal striatum are thought to be important for the regulation of movement. Because of the dopamine depletion in the striatum, movement is affected in PD. The typical motor symptoms consist of poverty of movement, tremor at rest, rigidity, and postural instability. Meanwhile, pre-motor symptoms, including hyposmia, constipation, depression, and REM sleep behavior disorder, have been suggested to precede these typical motor symptoms by years [2]. It is usually proposed to alleviate these symptoms via boosting the levels of dopamine in PD. However, this may not be the case.
基金This highlight article was supported by grants from the National Natural Science Foundation of China(31800893 and 31771124)Shandong Provincial Natural Science Foundation(ZR2019BC008).
文摘More and more evidence has suggested that iron deposition in the substantia nigra,which is correlated with motor and cognitive dysfunction,is an important trigger factor,potential biomarker,and therapeutic target for Parkinson's disease(PD)[1-3].Although the cellular mechanisms of nigral iron deposition have been well investigated,the exactly mechanisms,especially the origin of the increased nigral iron,have not been fully elucidated.
基金supported by grants from the National Foundation of Natural Science of China (31871049, 31771124, and 31800893)。
文摘Neuroinflammation and a-synuclein (a-syn) aggregation are both neuropathological hallmarks of Parkinson’s disease (PD). Microglia are crucial participants in eliciting neuroinflammatory responses themselves, as well as modulating neurotoxic activity in astrocytes, therefore forming a pathway to neurodegeneration induced by both central and peripheral insults [1, 2].
基金the National Natural Science Foundation of China(82071218,81630026,and 81930029).
文摘Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression.Discs large homolog 1(Dlg1),an adaptor protein,regulates cell polarization and the function of K?channels,which are reported to regulate the activation of microglia.However,little is known about the role of Dlg1 in microglia and the maintenance of central nervous system homeostasis.In this study,we found that Dlg1 knockdown suppressed lipopolysaccharide(LPS)-induced inflammation by downregulating the activation of nuclear factor-jB signaling and the mitogen-activated protein kinase pathway in microglia.Moreover,using an inducible Dlg1 microglia-specific knockout(Dlg1flox/flox;CX3CR1CreER)mouse line,we found that microglial Dlg1 knockout reduced the activation of microglia and alleviated the LPS-induced depressionlike behavior.In summary,our results demonstrated that Dlg1 plays a critical role in microglial activation and thus provides a potential therapeutic target for the clinical treatment of depression.
基金This insight was supported by the National Foundation of Natural Science of China(32170984)the Natural Science Foundation of Shandong Province(ZR2020YQ23 and ZR2019BC008).
文摘Disturbances of Ca^(2+)homeostasis have been reported to be associated with the development of Parkinson's disease(PD)(Fig.1),which is characterized by the selective vulnerability of dopaminergic neurons in the substantia nigra pars compacta(SNpc).Different from the dopaminergic neurons in the ventral tegmental area(VTA),which mainly rely on hyperpolarization-activated cyclic nucleotide-gated/voltagegated channels for pacing and have a strong Ca^(2+)-buffering capacity.
基金the National Natural Science Foundation of China(81830035)the China Postdoctoral Science Foundation(2019M662290)。
文摘Potassium ions(K+),the pivotal cations for membrane potential,are particularly important for maintaining the physiological function of neurons[1].When the concentration of extracellular K+([K+]o)is pathologically changed,the intrinsic neuronal excitability and synaptic transmission are also altered,which have profound implications for many neurological disorders such as epilepsy,Parkinson's disease,and emotional disorders[2-4].
基金This Highlight was supported by the National Natural Science Foundation of China(31871202,32170984)the Department of Science and Technology of Shandong Province(ZR2019MC057)+1 种基金Excellent Innovative Team of Shandong Province(2020KJK007)Taishan Scholars Construction Project of Shandong Province,China.
文摘Parkinson's disease(PD)is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc),accompanied by severe locomotor deficits[1].Deep brain stimulation(DBS)mainly targeting the subthalamic nucleus and the internal segment of the globus pallidus has now been clinically used to improve the motor symptoms of PD patients.However,these targets do not relieve the serious postural instability and freezing of gait.The mesencephalic locomotor region(MLR)plays a key role in controlling locomotion[2,3].
基金supported by Jiangsu Provincial Key Medical Center(No.YXZXA2016009)National Key Research and Development Program of China(No.2017YFA0701301)+2 种基金National Natural Science Foundation of China(No.22205127,21875101 and 22175085)Postgraduate Research&Practice Innovation Program of Jiangsu Province(SJCX22-0030)Jiangsu Funding Program for Excellent Postdoctoral Talent(NO.2022ZB692)。
文摘Wound healing has become one of the basic issues faced by the medical community because of the susceptibility of skin wounds to bacterial infection.As such,it is highly desired to design a nanocomposite hydrogel with excellent antibacterial activity to achieve high wound closure effectiveness.Here,based on ultrasound-triggered piezocatalytic therapy,a multifunctional hydrogel is designed to promote bacteria-infected wound healing.Under ultrasonic vibration,the surface of barium titanate(BaTiO_(3),BT)nanoparticles embedded in the hydrogel rapidly generate reactive oxygen species(ROS)owing to the established strong built-in electric field,endowing the hydrogel with superior antibacterial efficacy.This modality shows intriguing advantages over conventional photodynamic therapy,such as prominent soft tissue penetration ability and the avoidance of serious skin phototoxicity after systemic administration of photosensitizers.Moreover,the hydrogel based on N-[tris(hydroxymethyl)methyl]acrylamide(THM),N-(3-aminopropyl)methacrylamide hydrochloride(APMH)and oxidized hyaluronic acid(OHA)exhibits outstanding self-healing and bioadhesive properties able to accelerate full-thickness skin wound healing.Notably,compared with the widely reported mussel-inspired adhesive hydrogels,OHA/THM-APMH hydrogel due to the multiple hydrogen bonds from unique tri-hydroxyl structure overcomes the shortage that catechol groups are easily oxidized,giving it long-term and repeatable adhesion performance.Importantly,this hybrid hydrogel confines BT nanoparticles to wound area and locally induced piezoelectric catalysis under ultrasound to eradicate bacteria,markedly improving the therapeutic biosafety and exhibits great potential for harmless treatment of bacteria-infected tissues.
基金supported by the National Natural Science Foundation of China (31671054,31771124 and 81430024)the Postdoctoral Science Foundation of China (2017M610412 and 2018T110666)+1 种基金the Bureau of Science and Technology of Qingdao Municipality,China(17-1-1-44-jch)the Taishan Scholars Construction Project of Shandong Province, China。
文摘Dear Editor,Ghrelin,an endogenous ligand of growth hormone secretagogue receptor 1a(GHS-R1a),is a 28-amino-acid peptide that regulates growth hormone secretion,metabolism,food intake,mood,cognition,memory,and neuroprotection[1-3].