Parkinson’s disease can affect not only motor functions but also cognitive abilities,leading to cognitive impairment.One common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive ...Parkinson’s disease can affect not only motor functions but also cognitive abilities,leading to cognitive impairment.One common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive functioning.Executive functions help us plan,organize,and control our actions based on our goals.The brain area responsible for executive functions is called the prefrontal co rtex.It acts as the command center for the brain,especially when it comes to regulating executive functions.The role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called dopamine.However,little is known about how dopamine affects the cognitive functions of patients with Parkinson’s disease.In this article,the authors review the latest research on this topic.They start by looking at how the dopaminergic syste m,is alte red in Parkinson’s disease with executive dysfunction.Then,they explore how these changes in dopamine impact the synaptic structure,electrical activity,and connection components of the prefrontal cortex.The authors also summarize the relationship between Parkinson’s disease and dopamine-related cognitive issues.This information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson’s disease.展开更多
Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism....Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.展开更多
Melatonin and dopamine can potentially prevent waterlogging stress in apples.The current study investigated the mechanism by which melatonin and dopamine alleviate apple waterlogging stress.This study demonstrated tha...Melatonin and dopamine can potentially prevent waterlogging stress in apples.The current study investigated the mechanism by which melatonin and dopamine alleviate apple waterlogging stress.This study demonstrated that melatonin and dopamine alleviated waterlogging by removing reactive oxygen species(ROS),and that the nitric oxide(NO)content and nitrate reductase(NR)activity were significantly correlated.Melatonin and dopamine were also found to recruit different candidate beneficial endophytes(melatonin:Novosphingobium,Propionivibrio,and Cellvibrio;dopamine:Hydrogenophaga,Simplicispira,Methyloversatilis,Candidatus_Kaiserbacteria,and Humicola),and these endophytes were significantly and positively correlated with plant growth.Network analyses showed that melatonin and dopamine significantly affected the endophytic bacterial and fungal communities under waterlogging stress.The metabolomic results showed that melatonin and dopamine led to waterlogging resistance by upregulating the abundance of beneficial substances such as amino acids,flavonoids,coumarins,and organic acids.In addition,melatonin and dopamine regulated the physicochemical properties of the soil,which altered the endophyte community and affected plant growth.The co-occurrence network demonstrated close and complex relationships among endophytes,metabolites,soil,and the plants.Our results demonstrate that melatonin and dopamine alleviate waterlogging stress in apples by recruiting beneficial endophytes to enhance physiological resilience.This study provides new insights into how melatonin and dopamine alleviate stress and a theoretical basis for synergistic beneficial microbial resistance to waterlogging stress.展开更多
Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Cu...Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.展开更多
A novel strategy was developed to prepare the methacrylic gelatin-dopamine(GelMA-DA)/Ag nanoparticles(NPs)/graphene oxide(GO) composite hydrogels with good biocompatibility,mechanical properties,and antibacterial acti...A novel strategy was developed to prepare the methacrylic gelatin-dopamine(GelMA-DA)/Ag nanoparticles(NPs)/graphene oxide(GO) composite hydrogels with good biocompatibility,mechanical properties,and antibacterial activity.Mussel-inspired DA was utilized to modify the GelMA molecules,which imparts good adhesive performance to the hydrogels.GO,interfacial enhancer,not only improves mechanical properties of the hydrogels,but also provides anchor sites for loading Ag NPs through numerous oxygencontaining functional groups on the surface.The experimental results show that the GelMA/Ag NPs/GO hydrogels have good biocompatibility,and exhibit a swelling rate of 202±16%,the lap shear strength of 147±17 kPa,and compressive modulus of 136±53 kPa,in the case of the Ag NPs/GO content of 2 mg/mL.Antibacterial activity of the hydrogels against both gram-negative and gram-positive bacteria is dependent on the Ag NPs/GO content derived from the release of Ag^(+).Furthermore,the GelMA/Ag NPs/GO hydrogels possess good adhesive ability,which is resistant to highly twisted state when stuck on the surface of pigskin.These results demonstrate promising potential of the GelMA-DA/Ag NPs/GO hydrogels as wound dressings for biomedical applications in clinical and emergent treatment.展开更多
Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histo...Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.展开更多
AIM:To evaluate effects of endogenous dopamine induced by low concentration atropine eye drops on choroidal neovascularization(CNV)in high myopia mice.METHODS:The C57BL/6J mice were deprived of the right eye for 4wk,a...AIM:To evaluate effects of endogenous dopamine induced by low concentration atropine eye drops on choroidal neovascularization(CNV)in high myopia mice.METHODS:The C57BL/6J mice were deprived of the right eye for 4wk,and the high myopia was diagnosed by optometry,the diopter was less than-6.00 D,and CNV was induced by 532 nm laser.The changes of dopamine D1 receptor(DRD1),dopamine D2 receptor(DRD2),and vascular endothelial growth factor A(VEGFA)were detected by Western blot technology at 0.5,1,2h,and 7d after 0.01%,0.05%,and 0.1%atropine eye drops,respectively,the area of CNV was measured.RESULTS:Significant increases were observed on the expression of DRD2 in mouse high myopia model at 0.5,1,2h,7d with 0.05%and 0.1%atropine eye drops(P<0.05).Significant decreases were observed on the expression of DRD1 and VEGFA in mouse high myopia model at 0.5,1,2h,7d with 0.05%and 0.1%atropine eye drops(P<0.05).The area of CNV induced by laser in the drug-treated group was significantly smaller than that in the control group,and the higher the concentration,the more significant the inhibitory effect(P<0.05).CONCLUSION:The 0.01%,0.05%,0.1%atropine eye drops can decrease the level of VEGFA and inhibit high myopia CNV indirectly by up-regulating the level of DRD2 and down-regulating the level of DRD1,and the effect of 0.05%and 0.1%atropine eye drops is more significant.展开更多
Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relations...Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson’s disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson’s disease. We then established a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson’s disease.展开更多
The^(10)boron neutron-capture therapy(BNCT)is an emerging antitumoral method that shows increasing biomedical interest.BNCT is based on the selective accumulation of the^(10)boron isotope within the tumor,which is the...The^(10)boron neutron-capture therapy(BNCT)is an emerging antitumoral method that shows increasing biomedical interest.BNCT is based on the selective accumulation of the^(10)boron isotope within the tumor,which is then irradiated with low-energy thermal neutrons,generating nuclear fission that produces 7lithium,4helium,andγrays.Simple catechol-borate esters have been rather overlooked as precursors of melanin biosynthesis,and therefore,a proof-of-concept approach for using dopamine-borate(DABO)as a suitable boron-containing candidate for potential BNCT is presented here.DABO can spontaneously oxidize and autopolymerize in vitro,giving a soluble,eumelaninlike brown-black poly-DABO product.Melanotic melanoma cell cultures treated with 1 mM DABO for 24 and 48 h were viable and showed no signs of damage or cell death.The stability and possible trans-esterification of DABO is shortly discussed.Chemical calculations and quantitative structure-activity relationships(QSAR)analysis of DABO and the BNCT agent BPA indicated that they should be cell permeant and accumulate within lysosomes and melanosomes.Molecular modeling allows visualization of both the DABO precursor and the structure of a borate derivative of the proposed catechol-porphycene model for eumelanin,showing interesting features from molecular orbital calculations.The main difference between DABO and other agents,such as BPA,is that it is not a boronic acid nor a boron cluster.This simple catechol-borate ester(protected from oxidation and blackening)could be administrated to living cells and organisms,in which biosynthesis of boron-melanin in melanoma melanocytes can lead to improved BNCT.展开更多
Dopamine has demonstrated promise as a stress-relief substance.However,the function of dopamine in Cd tolerance and its mechanism remains largely unknown.The current study was performed to investigate the mechanism of...Dopamine has demonstrated promise as a stress-relief substance.However,the function of dopamine in Cd tolerance and its mechanism remains largely unknown.The current study was performed to investigate the mechanism of dopamine on alleviating apple Cd stress through regular application of CdCl2 and dopamine solution to potting soil.The results indicated that dopamine significantly reduced reactive oxygen species(ROS)and Cd accumulation and alleviated the inhibitory effect of Cd stress on the growth of apple plants through activation of the antioxidant system,enhancement of photosynthetic capacity,and regulation of gene expression related to Cd absorption and detoxification.The richness of the rhizosphere microbial community increased,and community composition and assembly were affected by dopamine treatment.Network analysis of microbial communities showed that the numbers of nodes and total links increased significantly after dopamine treatment,while the keystone species shifted.Linear discriminant analysis effect size indicated that some biomarkers were significantly enriched after dopamine treatment,suggesting that dopamine induced plants to recruit potentially beneficial microorganisms(Pseudoxanthomonas,Aeromicrobium,Bradyrhizobium,Frankia,Saccharimonadales,Novosphingobium,and Streptomyces)to resist Cd stress.The co-occurrence network showed several metabolites that were positively correlated with relative growth rate and negatively correlated with Cd accumulation,suggesting that potentially beneficial microorganisms may be attracted by several metabolites(L-threonic acid,profenamine,juniperic acid and(3β,5ξ,9ξ)-3,6,19-trihydroxyurs-12-en-28-oic acid).Our results demonstrate that dopamine alleviates Cd stress in apple trees by recruiting beneficial microorganisms to enhance the physiological resilience revealed.This study provides an effective means to reduce the harm to agricultural production caused by heavy metals.展开更多
BACKGROUND Dopamine and cyclic adenosine monophosphate(cAMP)-regulated phosphop-rotein with an apparent Mr of 32000(DARPP-32)is a protein that is involved in regulating dopamine and cAMP signaling pathways in the brai...BACKGROUND Dopamine and cyclic adenosine monophosphate(cAMP)-regulated phosphop-rotein with an apparent Mr of 32000(DARPP-32)is a protein that is involved in regulating dopamine and cAMP signaling pathways in the brain.However,recent studies have shown that DARPP-32 is also expressed in other tissues,including colorectal cancer(CRC),where its function is not well understood.AIM To explore the effect of DARPP-32 on CRC progression.METHODS The expression levels of DARPP-32 were assessed in CRC tissues using both quantitative polymerase chain reaction and immunohistochemistry assays.The proliferative capacity of CRC cell lines was evaluated with Cell Counting Kit-8 and 5-ethynyl-2’-deoxyuridine assays,while apoptosis was measured by flow cytometry.The migratory and invasive potential of CRC cell lines were deter-mined using wound healing and transwell chamber assays.In vivo studies involved monitoring the growth rate of xenograft tumors.Finally,the underlying molecular mechanism of DARPP-32 was investigated through RNA-sequencing and western blot analyses.RESULTS DARPP-32 was frequently upregulated in CRC and associated with abnormal clinicopathological features in CRC.Overexpression of DARPP-32 was shown to promote cancer cell proliferation,migration,and invasion and reduce apoptosis.DARPP-32 knockdown resulted in the opposite functional effects.Mechanistically,DARPP-32 may regulate the phosphoinositide 3-kinase(PI3K)/AKT signaling pathway in order to carry out its biological function.CONCLUSION DARPP-32 promotes CRC progression via the PI3K/AKT signaling pathway.展开更多
Astrocytes and astrocyte-related proteins play important roles in maintaining normal brain function,and also regulate pathological processes in brain diseases and injury.However,the role of astrocytes in the dopamine-...Astrocytes and astrocyte-related proteins play important roles in maintaining normal brain function,and also regulate pathological processes in brain diseases and injury.However,the role of astrocytes in the dopamine-depleted striatum remains unclear.A rat model of Parkinson’s disease was therefore established by injecting 10μL 6-hydroxydopamine(2.5μg/μL)into the right medial forebrain bundle.Immunohistochemical staining was used to detect the immunoreactivity of glial fibrillary acidic protein(GFAP),calcium-binding protein B(S100B),and signal transducer and activator of transcription 3(STAT3)in the striatum,and to investigate the co-expression of GFAP with S100B and STAT3.Western blot assay was used to measure the protein expression of GFAP,S100B,and STAT3 in the striatum.Results demonstrated that striatal GFAP-immunoreactive cells had an astrocytic appearance under normal conditions,but that dopamine depletion induced a reactive phenotype with obvious morphological changes.The normal striatum also contained S100B and STAT3 expression.S100B-immunoreactive cells were uniform in the striatum,with round bodies and sparse,thin processes.STAT3-immunoreactive cells presented round cell bodies with sparse processes,or were darkly stained with a large cell body.Dopamine deprivation induced by 6-hydroxydopamine significantly enhanced the immunohistochemical positive reaction of S100B and STAT3.Normal striatal astrocytes expressed both S100B and STAT3.Striatal dopamine deprivation increased the number of GFAP/S100B and GFAP/STAT3 double-labeled cells,and increased the protein levels of GFAP,S100B,and STAT3.The present results suggest that morphological changes in astrocytes and changes in expression levels of astrocyte-related proteins are involved in the pathological process of striatal dopamine depletion.The study was approved by Animal Care and Use Committee of Sun Yat-sen University,China(Zhongshan Medical Ethics 2014 No.23)on September 22,2014.展开更多
Accumulating studies suggest that neuroinflammation characterized by microglial overactivation plays a pivotal role in the pathogenesis of Parkinson’s disease.As such,inhibition of microglial overactivation might be ...Accumulating studies suggest that neuroinflammation characterized by microglial overactivation plays a pivotal role in the pathogenesis of Parkinson’s disease.As such,inhibition of microglial overactivation might be a promising treatment strategy to delay the onset or slow the progression of Parkinson’s disease.Ginsenoside Rbl,the most active ingredient of ginseng,reportedly exerts neuroprotective effects by suppressing inflammation in vitro.The present study aimed to evaluate the neuroprotective and anti-inflammatory effects of ginsenoside Rbl in a lipopolysaccharide-induced rat Parkinson’s disease model.Rats were divided into four groups.In the control group,sham-operated rats were intraperitoneally administered normal saline for 14 consecutive days.In the ginsenoside Rbl group,ginsenoside Rb1(20 mg/kg)was intraperitoneally injected for 14 consecutive days after sham surgery.In the lipopolysaccharide group,a single dose of lipopolysaccharide was unilaterally microinjected into the rat substantial nigra to establish the Parkinson’s disease model.Lipopolysaccharide-injected rats were treated with normal saline for 14 consecutive days.In the ginsenoside Rbl +lipopolysaccharide group,lipopolysaccharide was unilaterally microinjected into the rat substantial nigra.Subsequently,ginsenoside Rbl was intraperitoneally injected for 14 consecutive days.To investigate the therapeutic effects of ginsenoside Rbl,behavioral tests were performed on day 15 after lipopolysaccharide injection.We found that ginsenoside Rbl treatment remarkably reduced apomorphine-induced rotations in lipopolysaccharide-treated rats compared with the lipopolysaccharide group.To investigate the neurotoxicity of lipopolysaccharide and potential protective effect of ginsenoside Rbl,contents of dopamine and its metabolites in the striatum were measured by high-performance liquid chromatography.Compared with the lipopolysaccharide group,ginsenoside Rbl obviously attenuated the lipopolysaccharide-induced depletion of dopamine and its metabolites in the striatum.To further explore the neuroprotective effect of ginsenoside Rbl against lipopolysaccharide-induced neurotoxicity,immunohistochemistry and western blot assay of tyrosine hydroxylase were performed to evaluate dopaminergic neuron degeneration in the substantial nigra par compacta.The results showed that lipopolysaccharide injection caused a large loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra and a significant decrease in overall tyrosine hydroxylase expression.However,ginsenoside Rb1 noticeably reversed these changes.To investigate whether the neuroprotective effect of ginsenoside Rbl was associated with inhibition of lipopolysaccharide-induced microglial activation,we examined expression of the microglia marker Iba-1.Our results confirmed that lipopolysaccharide injection induced a significant increase in Iba-1 expression in the substantia nigra;however,ginsenoside Rbl effectively suppressed lipopolysaccharide-induced microglial overactivation.To elucidate the inhibitory mechanism of ginsenoside Rb1,we examined expression levels of inflammatory mediators(tumor necrosis factor-a,interleukin-1β,inducible nitric oxide synthase,and cyclooxygenase 2)and phosphorylation of nuclear factor kappa B signaling-related proteins(IκB,IKK)in the substantia nigra with enzyme-linked immunosorbent and western blot assays.Our results revealed that compared with the control group,phosphorylation and expression of inflammatory mediators IκB and IKK in the substantia nigra of lipopolysaccharide group rats were significantly increased;whereas,ginsenoside Rbl obviously reduced lipopolysaccharide-induced changes on the lesioned side of the substantial nigra par compacta.These findings confirm that ginsenoside Rbl can inhibit inflammation induced by lipopolysaccharide injection into the substantia nigra and protect dopaminergic neurons,which may be related to its inhibition of the nuclear factor kappa B signaling pathway.This study was approved by the Experimental Animal Ethics Committee of Shandong University of China in April 2016(approval No.KYLL-2016-0148).展开更多
The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesi...The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson’s disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson’s disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies.展开更多
Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders.Parkinson's disease(PD)is a common,chronic neurodegenerative...Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders.Parkinson's disease(PD)is a common,chronic neurodegenerative disorder hallmarked by localized degeneration of a specific set of dopaminergic neurons within a midbrain sub-region.The specific cell type and confined location of degenerating neurons make cell replacement therapy ideal for PD treatment since it mainly requires replenishment of lost dopaminergic neurons with fresh and functional ones.Endogenous as well as exogenous cell sources have been identified as candidate targets for cell replacement therapy in PD.In this review,umbilical cord mesenchymal stem cells(UCMSCs)are discussed as they provide an inexpensive unlimited reservoir differentiable towards functional dopaminergic neurons that potentially lead to long-lasting behavioral recovery in PD patients.We also present mi RNAs-mediated neuronal differentiation of UCMSCs.The UCMSCs bear a number of outstanding characteristics including their non-tumorigenic,low-immunogenic properties that make them ideal for cell replacement therapy purposes.Nevertheless,more investigations as well as controlled clinical trials are required to thoroughly confirm the efficacy of UCMSCs for therapeutic medical-grade applications in PD.展开更多
Astrocytes protect neurons by modulating neuronal function and survival.Astrocytes support neurons in several ways.They provide energy through the astrocyte-neuron lactate shuttle,protect neurons from excitotoxicity,a...Astrocytes protect neurons by modulating neuronal function and survival.Astrocytes support neurons in several ways.They provide energy through the astrocyte-neuron lactate shuttle,protect neurons from excitotoxicity,and internalize neuronal lipid droplets to degrade fatty acids for neuronal metabolic and synaptic support,as well as by their high capacity for glutamate uptake and the conversion of glutamate to glutamine.A recent reported astrocyte system for protection of dopamine neurons against the neurotoxic products of dopamine,such as aminochrome and other o-quinones,were generated under neuromelanin synthesis by oxidizing dopamine catechol structure.Astrocytes secrete glutathione transferase M2-2 through exosomes that transport this enzyme into dopaminergic neurons to protect these neurons against aminochrome neurotoxicity.The role of this new astrocyte protective mechanism in Parkinson´s disease is discussed.展开更多
In the present study, PC12 cells induced by 6-hydroxydopamine as a model of Parkinson's Disease, were used to investigate the protective effects of bone marrow-derived mesenchymal stem cells bone marrow-derived mesen...In the present study, PC12 cells induced by 6-hydroxydopamine as a model of Parkinson's Disease, were used to investigate the protective effects of bone marrow-derived mesenchymal stem cells bone marrow-derived mesenchymal stem cells against 6-hydroxydopamine-induced neurotoxicity and to verify whether the mechanism of action relates to abnormal a-synuclein accumulation in cells Results showed that co-culture with bone marrow-derived mesenchymal stem cells enhanced PC12 cell viability and dopamine secretion in a cell dose-dependent manner. MitoLight staining was used to confirm that PC12 cells co-cultured with bone marrow-derived mesenchymal stem cells demonstrate reduced levels of cell apoptosis. Immunocytochemistry and western blot analysis found the quantity of α-synuclein accumulation was significantly reduced in PC12 cell and bone marrow-derived mesenchymal stem cell co-cultures. These results indicate that bone marrow-derived mesenchymal stem cells can attenuate 6-hydroxydopamine-induced cytotoxicity by reducing abnormal α-synuclein accumulation in PC12 cells.展开更多
Dopamine and its receptors have been widely studied in the neurological conditions and in the retina. In this study, we evaluated the possible role of dopamine in rhegmatogenous retinal detachment(RRD) by comparing th...Dopamine and its receptors have been widely studied in the neurological conditions and in the retina. In this study, we evaluated the possible role of dopamine in rhegmatogenous retinal detachment(RRD) by comparing the amount of 3,4-dihydroxyphenylacetic acid(DOPAC), a surrogate index of retinal dopamin levels, in the vitreous sample of patients affected by RRD with those affected by macular pucker and vitre ous hemorrhage. Our results showed that significantly higher levels of DOPAC were found in the vitreou sample of patients affected by RRD compared with those affected by vitreous hemorrhage and macula pucker(P = 0.002). Specifically, no trace of the substance was found in vitreous hemorrhage and macula pucker samples. A slightly significant positive correlation was found among DOPAC and post-operativ best corrected visual acuity(r = 0.470, P = 0.049). No correlation was found between DOPAC and the day elapsed between diagnosis and surgery(P = 0.317). For the first time our findings suggest that DOPAC i released in RRD, but not in other retinal diseases such as vitreous hemorrhage and macular pucker. More over, we showed a correlation between visual acuity outcome and the amount of DOPAC in the vitreous This might have a potential, although still unknown, implication in the pathogenesis of the disease and/o in the associated photoreceptors loss. This study was approved by the Ethics Committee of Rome Tor Ver gata University Hospital(R.S.92.10) on September 24, 2010.展开更多
Impairment of dopamine function, which is known to have major effects on behaviors and cognition, is one of the main problems associated with cerebral ischemia. Tadalafil, a long-acting phosphodiesterase type-5 inhibi...Impairment of dopamine function, which is known to have major effects on behaviors and cognition, is one of the main problems associated with cerebral ischemia. Tadalafil, a long-acting phosphodiesterase type-5 inhibitor, is known to ameliorate neurologic impairment induced by brain injury, but not in dopaminergic regions. We investigated the neuroprotective effects of treatment with tadalafil on cyclic guanosine monophosphate level and dopamine function following cerebral ischemia. Forty adult Mongolian gerbils were randomly and evenly divided into five groups (n = 8 in each group): Sham-operation group, cerebral ischemia-induced and 0, 0.1, 1, and 10 mg/kg tadalafil-treated groups, respectively. Tadalafil dissolved in distilled water was administered orally for 7 consecutive days, starting 1 day after surgery. Cyclic guanosine monophosphate assay and immunohistochemistry were performed for thyrosine hydroxylase expression and western blot analysis for dopamine D2 receptor expression. A decrease in cyclic guanosine monophosphate level following cerebral ischemia was found with an increase in thyrosine hydroxylase activity and a decrease in dopamine D2 receptor expression in the striatum and substantia nigra region. However, treatment with tadalafil increased cyclic guanosine monophosphate expression, suppressed thyrosine hydroxylase expression and increased dopamine 92 receptor expression in the striatum and substantia nigra region in a dose-dependent manner. Tadalafil might ameliorate cerebral ischemia-induced dopaminergic neuron injury. Therefore, tadalafil has the potential as a new neuroprotective treatment strategy for cerebral ischemic injury.展开更多
Fibromyalgia(FM) is a complex pathology described as persistent hyperalgesia including somatic and mood dysfunctions, depression and anxiety. Although the etiology of FM is still unknown, a significant decrease in bio...Fibromyalgia(FM) is a complex pathology described as persistent hyperalgesia including somatic and mood dysfunctions, depression and anxiety. Although the etiology of FM is still unknown, a significant decrease in biogenic amines is a common characteristic in its pathogenesis. Here, our main objective was to investigate the role of dopamine D3/D2 receptor during the reserpine-induced pain in mice. Our results showed that pramipexole(PPX) – a dopaminergic D3/D2 receptor agonist – inhibited mechanical allodynia and thermal sensitivity induced by reserpine. Relevantly, PPX treatment decreased immobility time and increased the number of grooming in the forced swimming test and splash test, respectively. Animals that received PPX remained longer in the open arms than the reserpine group using elevated plusmaze apparatus. The repeated PPX administration, given daily for 4 days, significantly blocked the mechanical and thermal allodynia during FM model, similarly to pregabalin, although it failed to affect the reserpine-induced thermal nociception. Reserpine administration induced significant downregulation of dopamine concentration in the central nervous system, and repeated treatment with PPX restored dopamine levels in the frontal cortex and spinal cord tissues. Moreover, PPX treatment inhibited oxidants production such as DCFH(2′,7′-dichlorodihydrofluorescein) and nitrite, also decreased oxidative damage(carbonyl), and upregulated the activity of superoxide dismutase in the spinal cord. Together, our findings demonstrated the ability of dopamine D3/D2 receptor-preferring agonist in reducing pain and mood dysfunction allied to FM in mice. All experimental protocols were approved by the Universidade Federal de Santa Catarina(UFSC) Ethics Committee(approval No. 2572210218) on May 10, 2018.展开更多
基金supported by the National Natural Science Foundation of China,No.82101263Jiangsu Province Science Foundation for Youths,No.BK20210903Research Foundation for Talented Scholars of Xuzhou Medical University,No.RC20552114(all to CT)。
文摘Parkinson’s disease can affect not only motor functions but also cognitive abilities,leading to cognitive impairment.One common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive functioning.Executive functions help us plan,organize,and control our actions based on our goals.The brain area responsible for executive functions is called the prefrontal co rtex.It acts as the command center for the brain,especially when it comes to regulating executive functions.The role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called dopamine.However,little is known about how dopamine affects the cognitive functions of patients with Parkinson’s disease.In this article,the authors review the latest research on this topic.They start by looking at how the dopaminergic syste m,is alte red in Parkinson’s disease with executive dysfunction.Then,they explore how these changes in dopamine impact the synaptic structure,electrical activity,and connection components of the prefrontal cortex.The authors also summarize the relationship between Parkinson’s disease and dopamine-related cognitive issues.This information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson’s disease.
基金supported by the Research Project of the Shanghai Health Commission,No.2020YJZX0111(to CZ)the National Natural Science Foundation of China,Nos.82021002(to CZ),82272039(to CZ),82171252(to FL)+1 种基金a grant from the National Health Commission of People’s Republic of China(PRC),No.Pro20211231084249000238(to JW)Medical Innovation Research Project of Shanghai Science and Technology Commission,No.21Y11903300(to JG).
文摘Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.
基金supported by the National Natural Science Foundation of China(31901964)the Natural Science Foundation of Hebei,China(C2021204158)+3 种基金the Science and Technology Project of Hebei Education Department,China(BJK2022012)the Introduced Talents Project of Hebei Agricultural University,China(YJ201904)the earmarked fund for Hebei Apple Innovation Team of Modern Agroindustry Technology Research System,China(HBCT2024150205)the earmarked fund for the China Agricultural Research System,China(CARS-27).
文摘Melatonin and dopamine can potentially prevent waterlogging stress in apples.The current study investigated the mechanism by which melatonin and dopamine alleviate apple waterlogging stress.This study demonstrated that melatonin and dopamine alleviated waterlogging by removing reactive oxygen species(ROS),and that the nitric oxide(NO)content and nitrate reductase(NR)activity were significantly correlated.Melatonin and dopamine were also found to recruit different candidate beneficial endophytes(melatonin:Novosphingobium,Propionivibrio,and Cellvibrio;dopamine:Hydrogenophaga,Simplicispira,Methyloversatilis,Candidatus_Kaiserbacteria,and Humicola),and these endophytes were significantly and positively correlated with plant growth.Network analyses showed that melatonin and dopamine significantly affected the endophytic bacterial and fungal communities under waterlogging stress.The metabolomic results showed that melatonin and dopamine led to waterlogging resistance by upregulating the abundance of beneficial substances such as amino acids,flavonoids,coumarins,and organic acids.In addition,melatonin and dopamine regulated the physicochemical properties of the soil,which altered the endophyte community and affected plant growth.The co-occurrence network demonstrated close and complex relationships among endophytes,metabolites,soil,and the plants.Our results demonstrate that melatonin and dopamine alleviate waterlogging stress in apples by recruiting beneficial endophytes to enhance physiological resilience.This study provides new insights into how melatonin and dopamine alleviate stress and a theoretical basis for synergistic beneficial microbial resistance to waterlogging stress.
基金supported by the National Natural Science Foundation of China,No.82071254(to WZ).
文摘Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.
基金Funded by the National Key Research and Development(R&D) Program of China(No.2018YFB1105702)。
文摘A novel strategy was developed to prepare the methacrylic gelatin-dopamine(GelMA-DA)/Ag nanoparticles(NPs)/graphene oxide(GO) composite hydrogels with good biocompatibility,mechanical properties,and antibacterial activity.Mussel-inspired DA was utilized to modify the GelMA molecules,which imparts good adhesive performance to the hydrogels.GO,interfacial enhancer,not only improves mechanical properties of the hydrogels,but also provides anchor sites for loading Ag NPs through numerous oxygencontaining functional groups on the surface.The experimental results show that the GelMA/Ag NPs/GO hydrogels have good biocompatibility,and exhibit a swelling rate of 202±16%,the lap shear strength of 147±17 kPa,and compressive modulus of 136±53 kPa,in the case of the Ag NPs/GO content of 2 mg/mL.Antibacterial activity of the hydrogels against both gram-negative and gram-positive bacteria is dependent on the Ag NPs/GO content derived from the release of Ag^(+).Furthermore,the GelMA/Ag NPs/GO hydrogels possess good adhesive ability,which is resistant to highly twisted state when stuck on the surface of pigskin.These results demonstrate promising potential of the GelMA-DA/Ag NPs/GO hydrogels as wound dressings for biomedical applications in clinical and emergent treatment.
基金supported by an under-40 grant from the Italian Association for Alzheimer’s Research [AIRALZH AGYR2021]the Strategic University Projects–Young Researcher Independence grant [YRG2021] from the Università Campus Bio-Medico di Roma (Rome, Italy)(to LLB)+1 种基金Italian Ministry of Health [Research Grant:GR-2019-12370446]the American Alzheimer’s Association [AARG-22-922961](to PK)。
文摘Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.
文摘AIM:To evaluate effects of endogenous dopamine induced by low concentration atropine eye drops on choroidal neovascularization(CNV)in high myopia mice.METHODS:The C57BL/6J mice were deprived of the right eye for 4wk,and the high myopia was diagnosed by optometry,the diopter was less than-6.00 D,and CNV was induced by 532 nm laser.The changes of dopamine D1 receptor(DRD1),dopamine D2 receptor(DRD2),and vascular endothelial growth factor A(VEGFA)were detected by Western blot technology at 0.5,1,2h,and 7d after 0.01%,0.05%,and 0.1%atropine eye drops,respectively,the area of CNV was measured.RESULTS:Significant increases were observed on the expression of DRD2 in mouse high myopia model at 0.5,1,2h,7d with 0.05%and 0.1%atropine eye drops(P<0.05).Significant decreases were observed on the expression of DRD1 and VEGFA in mouse high myopia model at 0.5,1,2h,7d with 0.05%and 0.1%atropine eye drops(P<0.05).The area of CNV induced by laser in the drug-treated group was significantly smaller than that in the control group,and the higher the concentration,the more significant the inhibitory effect(P<0.05).CONCLUSION:The 0.01%,0.05%,0.1%atropine eye drops can decrease the level of VEGFA and inhibit high myopia CNV indirectly by up-regulating the level of DRD2 and down-regulating the level of DRD1,and the effect of 0.05%and 0.1%atropine eye drops is more significant.
基金supported by the National Natural Science Foundation of China,Nos. 81971006 (to DSG), 82101263 (to CXT)Jiangsu Province Science Foundation for Youths,No. BK20210903 (to CXT)+2 种基金Research Foundation for Talented Scholars of Xuzhou Medical University,No. RC20552114 (to CXT)Science&Technology Program of Xuzhou,No. KC19016 (to JC)Project of Xuzhou Medical University,No. 2018KJ06 (to JC)。
文摘Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson’s disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson’s disease. We then established a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson’s disease.
文摘The^(10)boron neutron-capture therapy(BNCT)is an emerging antitumoral method that shows increasing biomedical interest.BNCT is based on the selective accumulation of the^(10)boron isotope within the tumor,which is then irradiated with low-energy thermal neutrons,generating nuclear fission that produces 7lithium,4helium,andγrays.Simple catechol-borate esters have been rather overlooked as precursors of melanin biosynthesis,and therefore,a proof-of-concept approach for using dopamine-borate(DABO)as a suitable boron-containing candidate for potential BNCT is presented here.DABO can spontaneously oxidize and autopolymerize in vitro,giving a soluble,eumelaninlike brown-black poly-DABO product.Melanotic melanoma cell cultures treated with 1 mM DABO for 24 and 48 h were viable and showed no signs of damage or cell death.The stability and possible trans-esterification of DABO is shortly discussed.Chemical calculations and quantitative structure-activity relationships(QSAR)analysis of DABO and the BNCT agent BPA indicated that they should be cell permeant and accumulate within lysosomes and melanosomes.Molecular modeling allows visualization of both the DABO precursor and the structure of a borate derivative of the proposed catechol-porphycene model for eumelanin,showing interesting features from molecular orbital calculations.The main difference between DABO and other agents,such as BPA,is that it is not a boronic acid nor a boron cluster.This simple catechol-borate ester(protected from oxidation and blackening)could be administrated to living cells and organisms,in which biosynthesis of boron-melanin in melanoma melanocytes can lead to improved BNCT.
基金This work was supported by the National Natural Science Foundation of China(No.31901964)the Science and Technology Project of Hebei Education Department(No.BJK2022012)the Earmarked fund for the China Agricultural Research System(No.CARS-27).
文摘Dopamine has demonstrated promise as a stress-relief substance.However,the function of dopamine in Cd tolerance and its mechanism remains largely unknown.The current study was performed to investigate the mechanism of dopamine on alleviating apple Cd stress through regular application of CdCl2 and dopamine solution to potting soil.The results indicated that dopamine significantly reduced reactive oxygen species(ROS)and Cd accumulation and alleviated the inhibitory effect of Cd stress on the growth of apple plants through activation of the antioxidant system,enhancement of photosynthetic capacity,and regulation of gene expression related to Cd absorption and detoxification.The richness of the rhizosphere microbial community increased,and community composition and assembly were affected by dopamine treatment.Network analysis of microbial communities showed that the numbers of nodes and total links increased significantly after dopamine treatment,while the keystone species shifted.Linear discriminant analysis effect size indicated that some biomarkers were significantly enriched after dopamine treatment,suggesting that dopamine induced plants to recruit potentially beneficial microorganisms(Pseudoxanthomonas,Aeromicrobium,Bradyrhizobium,Frankia,Saccharimonadales,Novosphingobium,and Streptomyces)to resist Cd stress.The co-occurrence network showed several metabolites that were positively correlated with relative growth rate and negatively correlated with Cd accumulation,suggesting that potentially beneficial microorganisms may be attracted by several metabolites(L-threonic acid,profenamine,juniperic acid and(3β,5ξ,9ξ)-3,6,19-trihydroxyurs-12-en-28-oic acid).Our results demonstrate that dopamine alleviates Cd stress in apple trees by recruiting beneficial microorganisms to enhance the physiological resilience revealed.This study provides an effective means to reduce the harm to agricultural production caused by heavy metals.
基金Supported by Chongqing Key Diseases Research and Application Demonstration Program,No.2019ZX003General Project of Chongqing Nature Science Foundation,No.cstc2021jcyj-msxmX0283.
文摘BACKGROUND Dopamine and cyclic adenosine monophosphate(cAMP)-regulated phosphop-rotein with an apparent Mr of 32000(DARPP-32)is a protein that is involved in regulating dopamine and cAMP signaling pathways in the brain.However,recent studies have shown that DARPP-32 is also expressed in other tissues,including colorectal cancer(CRC),where its function is not well understood.AIM To explore the effect of DARPP-32 on CRC progression.METHODS The expression levels of DARPP-32 were assessed in CRC tissues using both quantitative polymerase chain reaction and immunohistochemistry assays.The proliferative capacity of CRC cell lines was evaluated with Cell Counting Kit-8 and 5-ethynyl-2’-deoxyuridine assays,while apoptosis was measured by flow cytometry.The migratory and invasive potential of CRC cell lines were deter-mined using wound healing and transwell chamber assays.In vivo studies involved monitoring the growth rate of xenograft tumors.Finally,the underlying molecular mechanism of DARPP-32 was investigated through RNA-sequencing and western blot analyses.RESULTS DARPP-32 was frequently upregulated in CRC and associated with abnormal clinicopathological features in CRC.Overexpression of DARPP-32 was shown to promote cancer cell proliferation,migration,and invasion and reduce apoptosis.DARPP-32 knockdown resulted in the opposite functional effects.Mechanistically,DARPP-32 may regulate the phosphoinositide 3-kinase(PI3K)/AKT signaling pathway in order to carry out its biological function.CONCLUSION DARPP-32 promotes CRC progression via the PI3K/AKT signaling pathway.
基金supported by the National Natural Science Foundation of China,No.81471288(to WLL)the National High Technology Research and Development Program of China(863 Program),No.2017YFA0104704(to WLL)
文摘Astrocytes and astrocyte-related proteins play important roles in maintaining normal brain function,and also regulate pathological processes in brain diseases and injury.However,the role of astrocytes in the dopamine-depleted striatum remains unclear.A rat model of Parkinson’s disease was therefore established by injecting 10μL 6-hydroxydopamine(2.5μg/μL)into the right medial forebrain bundle.Immunohistochemical staining was used to detect the immunoreactivity of glial fibrillary acidic protein(GFAP),calcium-binding protein B(S100B),and signal transducer and activator of transcription 3(STAT3)in the striatum,and to investigate the co-expression of GFAP with S100B and STAT3.Western blot assay was used to measure the protein expression of GFAP,S100B,and STAT3 in the striatum.Results demonstrated that striatal GFAP-immunoreactive cells had an astrocytic appearance under normal conditions,but that dopamine depletion induced a reactive phenotype with obvious morphological changes.The normal striatum also contained S100B and STAT3 expression.S100B-immunoreactive cells were uniform in the striatum,with round bodies and sparse,thin processes.STAT3-immunoreactive cells presented round cell bodies with sparse processes,or were darkly stained with a large cell body.Dopamine deprivation induced by 6-hydroxydopamine significantly enhanced the immunohistochemical positive reaction of S100B and STAT3.Normal striatal astrocytes expressed both S100B and STAT3.Striatal dopamine deprivation increased the number of GFAP/S100B and GFAP/STAT3 double-labeled cells,and increased the protein levels of GFAP,S100B,and STAT3.The present results suggest that morphological changes in astrocytes and changes in expression levels of astrocyte-related proteins are involved in the pathological process of striatal dopamine depletion.The study was approved by Animal Care and Use Committee of Sun Yat-sen University,China(Zhongshan Medical Ethics 2014 No.23)on September 22,2014.
基金supported by the Medical and Health Technology Development Plan of Shandong Province of China,No.2011HD009(to AHW)the Chinese Medicine Science and Technology Development Plan Project of Shandong Province of China,No.2017-163(to AHW)+1 种基金the Natural Science Foundation of Shandong Province of China,No.ZR2016HP23(to AHW)the Science and Technology Development Plan Project of Taian City of China,No.2017NS0151(to XCS)
文摘Accumulating studies suggest that neuroinflammation characterized by microglial overactivation plays a pivotal role in the pathogenesis of Parkinson’s disease.As such,inhibition of microglial overactivation might be a promising treatment strategy to delay the onset or slow the progression of Parkinson’s disease.Ginsenoside Rbl,the most active ingredient of ginseng,reportedly exerts neuroprotective effects by suppressing inflammation in vitro.The present study aimed to evaluate the neuroprotective and anti-inflammatory effects of ginsenoside Rbl in a lipopolysaccharide-induced rat Parkinson’s disease model.Rats were divided into four groups.In the control group,sham-operated rats were intraperitoneally administered normal saline for 14 consecutive days.In the ginsenoside Rbl group,ginsenoside Rb1(20 mg/kg)was intraperitoneally injected for 14 consecutive days after sham surgery.In the lipopolysaccharide group,a single dose of lipopolysaccharide was unilaterally microinjected into the rat substantial nigra to establish the Parkinson’s disease model.Lipopolysaccharide-injected rats were treated with normal saline for 14 consecutive days.In the ginsenoside Rbl +lipopolysaccharide group,lipopolysaccharide was unilaterally microinjected into the rat substantial nigra.Subsequently,ginsenoside Rbl was intraperitoneally injected for 14 consecutive days.To investigate the therapeutic effects of ginsenoside Rbl,behavioral tests were performed on day 15 after lipopolysaccharide injection.We found that ginsenoside Rbl treatment remarkably reduced apomorphine-induced rotations in lipopolysaccharide-treated rats compared with the lipopolysaccharide group.To investigate the neurotoxicity of lipopolysaccharide and potential protective effect of ginsenoside Rbl,contents of dopamine and its metabolites in the striatum were measured by high-performance liquid chromatography.Compared with the lipopolysaccharide group,ginsenoside Rbl obviously attenuated the lipopolysaccharide-induced depletion of dopamine and its metabolites in the striatum.To further explore the neuroprotective effect of ginsenoside Rbl against lipopolysaccharide-induced neurotoxicity,immunohistochemistry and western blot assay of tyrosine hydroxylase were performed to evaluate dopaminergic neuron degeneration in the substantial nigra par compacta.The results showed that lipopolysaccharide injection caused a large loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra and a significant decrease in overall tyrosine hydroxylase expression.However,ginsenoside Rb1 noticeably reversed these changes.To investigate whether the neuroprotective effect of ginsenoside Rbl was associated with inhibition of lipopolysaccharide-induced microglial activation,we examined expression of the microglia marker Iba-1.Our results confirmed that lipopolysaccharide injection induced a significant increase in Iba-1 expression in the substantia nigra;however,ginsenoside Rbl effectively suppressed lipopolysaccharide-induced microglial overactivation.To elucidate the inhibitory mechanism of ginsenoside Rb1,we examined expression levels of inflammatory mediators(tumor necrosis factor-a,interleukin-1β,inducible nitric oxide synthase,and cyclooxygenase 2)and phosphorylation of nuclear factor kappa B signaling-related proteins(IκB,IKK)in the substantia nigra with enzyme-linked immunosorbent and western blot assays.Our results revealed that compared with the control group,phosphorylation and expression of inflammatory mediators IκB and IKK in the substantia nigra of lipopolysaccharide group rats were significantly increased;whereas,ginsenoside Rbl obviously reduced lipopolysaccharide-induced changes on the lesioned side of the substantial nigra par compacta.These findings confirm that ginsenoside Rbl can inhibit inflammation induced by lipopolysaccharide injection into the substantia nigra and protect dopaminergic neurons,which may be related to its inhibition of the nuclear factor kappa B signaling pathway.This study was approved by the Experimental Animal Ethics Committee of Shandong University of China in April 2016(approval No.KYLL-2016-0148).
基金supported by a Research Development Fund(UTS Start-Up Grant 2018)from the University of Technology Sydney to AC。
文摘The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson’s disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson’s disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies.
文摘Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders.Parkinson's disease(PD)is a common,chronic neurodegenerative disorder hallmarked by localized degeneration of a specific set of dopaminergic neurons within a midbrain sub-region.The specific cell type and confined location of degenerating neurons make cell replacement therapy ideal for PD treatment since it mainly requires replenishment of lost dopaminergic neurons with fresh and functional ones.Endogenous as well as exogenous cell sources have been identified as candidate targets for cell replacement therapy in PD.In this review,umbilical cord mesenchymal stem cells(UCMSCs)are discussed as they provide an inexpensive unlimited reservoir differentiable towards functional dopaminergic neurons that potentially lead to long-lasting behavioral recovery in PD patients.We also present mi RNAs-mediated neuronal differentiation of UCMSCs.The UCMSCs bear a number of outstanding characteristics including their non-tumorigenic,low-immunogenic properties that make them ideal for cell replacement therapy purposes.Nevertheless,more investigations as well as controlled clinical trials are required to thoroughly confirm the efficacy of UCMSCs for therapeutic medical-grade applications in PD.
基金supported by ANID-FONDECYT 1170033(to JSA)ANID-STINT-CONICYT CS2018-7940(to JSA,IN,JI,MV)Swedish Research Council grant 2015-04222 to BM.
文摘Astrocytes protect neurons by modulating neuronal function and survival.Astrocytes support neurons in several ways.They provide energy through the astrocyte-neuron lactate shuttle,protect neurons from excitotoxicity,and internalize neuronal lipid droplets to degrade fatty acids for neuronal metabolic and synaptic support,as well as by their high capacity for glutamate uptake and the conversion of glutamate to glutamine.A recent reported astrocyte system for protection of dopamine neurons against the neurotoxic products of dopamine,such as aminochrome and other o-quinones,were generated under neuromelanin synthesis by oxidizing dopamine catechol structure.Astrocytes secrete glutathione transferase M2-2 through exosomes that transport this enzyme into dopaminergic neurons to protect these neurons against aminochrome neurotoxicity.The role of this new astrocyte protective mechanism in Parkinson´s disease is discussed.
基金supported by the Science and Technology Development Foundation of Beijing Science and Technology Commission, No. Z101107052210004
文摘In the present study, PC12 cells induced by 6-hydroxydopamine as a model of Parkinson's Disease, were used to investigate the protective effects of bone marrow-derived mesenchymal stem cells bone marrow-derived mesenchymal stem cells against 6-hydroxydopamine-induced neurotoxicity and to verify whether the mechanism of action relates to abnormal a-synuclein accumulation in cells Results showed that co-culture with bone marrow-derived mesenchymal stem cells enhanced PC12 cell viability and dopamine secretion in a cell dose-dependent manner. MitoLight staining was used to confirm that PC12 cells co-cultured with bone marrow-derived mesenchymal stem cells demonstrate reduced levels of cell apoptosis. Immunocytochemistry and western blot analysis found the quantity of α-synuclein accumulation was significantly reduced in PC12 cell and bone marrow-derived mesenchymal stem cell co-cultures. These results indicate that bone marrow-derived mesenchymal stem cells can attenuate 6-hydroxydopamine-induced cytotoxicity by reducing abnormal α-synuclein accumulation in PC12 cells.
文摘Dopamine and its receptors have been widely studied in the neurological conditions and in the retina. In this study, we evaluated the possible role of dopamine in rhegmatogenous retinal detachment(RRD) by comparing the amount of 3,4-dihydroxyphenylacetic acid(DOPAC), a surrogate index of retinal dopamin levels, in the vitreous sample of patients affected by RRD with those affected by macular pucker and vitre ous hemorrhage. Our results showed that significantly higher levels of DOPAC were found in the vitreou sample of patients affected by RRD compared with those affected by vitreous hemorrhage and macula pucker(P = 0.002). Specifically, no trace of the substance was found in vitreous hemorrhage and macula pucker samples. A slightly significant positive correlation was found among DOPAC and post-operativ best corrected visual acuity(r = 0.470, P = 0.049). No correlation was found between DOPAC and the day elapsed between diagnosis and surgery(P = 0.317). For the first time our findings suggest that DOPAC i released in RRD, but not in other retinal diseases such as vitreous hemorrhage and macular pucker. More over, we showed a correlation between visual acuity outcome and the amount of DOPAC in the vitreous This might have a potential, although still unknown, implication in the pathogenesis of the disease and/o in the associated photoreceptors loss. This study was approved by the Ethics Committee of Rome Tor Ver gata University Hospital(R.S.92.10) on September 24, 2010.
基金supported by the Research Fund of Gachon University Gil Medical Center in 2011the National Research Foundation of Korea funded by the Korean Government,No. 2012R1A1A1013173
文摘Impairment of dopamine function, which is known to have major effects on behaviors and cognition, is one of the main problems associated with cerebral ischemia. Tadalafil, a long-acting phosphodiesterase type-5 inhibitor, is known to ameliorate neurologic impairment induced by brain injury, but not in dopaminergic regions. We investigated the neuroprotective effects of treatment with tadalafil on cyclic guanosine monophosphate level and dopamine function following cerebral ischemia. Forty adult Mongolian gerbils were randomly and evenly divided into five groups (n = 8 in each group): Sham-operation group, cerebral ischemia-induced and 0, 0.1, 1, and 10 mg/kg tadalafil-treated groups, respectively. Tadalafil dissolved in distilled water was administered orally for 7 consecutive days, starting 1 day after surgery. Cyclic guanosine monophosphate assay and immunohistochemistry were performed for thyrosine hydroxylase expression and western blot analysis for dopamine D2 receptor expression. A decrease in cyclic guanosine monophosphate level following cerebral ischemia was found with an increase in thyrosine hydroxylase activity and a decrease in dopamine D2 receptor expression in the striatum and substantia nigra region. However, treatment with tadalafil increased cyclic guanosine monophosphate expression, suppressed thyrosine hydroxylase expression and increased dopamine 92 receptor expression in the striatum and substantia nigra region in a dose-dependent manner. Tadalafil might ameliorate cerebral ischemia-induced dopaminergic neuron injury. Therefore, tadalafil has the potential as a new neuroprotective treatment strategy for cerebral ischemic injury.
基金supported by grants from Programa de Pos-graduacao em Neurociencias(PGN),Programa INCT-INOVAMED(grant No.465430/2014-7)Fundacao de Apoio à Pesquisa e Inovacao do Estado de Santa Catarina(FAPESC)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior(CAPES)。
文摘Fibromyalgia(FM) is a complex pathology described as persistent hyperalgesia including somatic and mood dysfunctions, depression and anxiety. Although the etiology of FM is still unknown, a significant decrease in biogenic amines is a common characteristic in its pathogenesis. Here, our main objective was to investigate the role of dopamine D3/D2 receptor during the reserpine-induced pain in mice. Our results showed that pramipexole(PPX) – a dopaminergic D3/D2 receptor agonist – inhibited mechanical allodynia and thermal sensitivity induced by reserpine. Relevantly, PPX treatment decreased immobility time and increased the number of grooming in the forced swimming test and splash test, respectively. Animals that received PPX remained longer in the open arms than the reserpine group using elevated plusmaze apparatus. The repeated PPX administration, given daily for 4 days, significantly blocked the mechanical and thermal allodynia during FM model, similarly to pregabalin, although it failed to affect the reserpine-induced thermal nociception. Reserpine administration induced significant downregulation of dopamine concentration in the central nervous system, and repeated treatment with PPX restored dopamine levels in the frontal cortex and spinal cord tissues. Moreover, PPX treatment inhibited oxidants production such as DCFH(2′,7′-dichlorodihydrofluorescein) and nitrite, also decreased oxidative damage(carbonyl), and upregulated the activity of superoxide dismutase in the spinal cord. Together, our findings demonstrated the ability of dopamine D3/D2 receptor-preferring agonist in reducing pain and mood dysfunction allied to FM in mice. All experimental protocols were approved by the Universidade Federal de Santa Catarina(UFSC) Ethics Committee(approval No. 2572210218) on May 10, 2018.