The search fo r reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis,to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies.Desp...The search fo r reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis,to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies.Despite the need for non-invasively accessible biomarke rs,the majo rity of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers,which require invasive collection procedures.Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers.In the present study,after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease,we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients.A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289articles.After screening and exclusion,34 relevant articles were derived fo r systematic review.Alpha-synuclein,the histopathological hallmark of Parkinson's disease,has been the most investigated Parkinson's disease biomarker in saliva,with oligomeric alphasynuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls,while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein,and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease.Beyond alpha-synuclein,other biomarkers to rgeting diffe rent molecular pathways have been explored in the saliva of Parkinson's disease patients:total tau,phosphorylated tau,amyloid-β1-42(pathological protein aggregation biomarkers);DJ-1,heme-oxygenase-l,metabolites(alte red energy homeostasis biomarkers);MAPLC-3beta(aberrant proteostasis biomarker);cortisol,tumor necrosis factor-alpha(inflammation biomarkers);DNA methylation,miRNA(DNA/RNA defects biomarkers);acetylcholinesterase activity(synaptic and neuronal network dysfunction biomarkers);Raman spectra,proteome,and caffeine.Despite a few studies investigating biomarkers to rgeting molecular pathways different from alpha-synuclein in Parkinson's disease,these results should be replicated and observed in studies on larger cohorts,considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes.Although the need fo r standardization in sample collection and processing,salivary-based biomarkers studies have reported encouraging results,calling for large-scale longitudinal studies and multicentric assessments,given the great molecular potentials and the non-invasive accessibility of saliva.展开更多
This comprehensive review explores the intricate relationship between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the context of the gut-brain axis.The gut-brain axis plays a pivot...This comprehensive review explores the intricate relationship between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the context of the gut-brain axis.The gut-brain axis plays a pivotal role in neurodegenerative diseases like Parkinson's disease,encompassing diverse components such as the gut microbiota,immune system,metabolism,and neural pathways.The gut microbiome,profoundly influenced by dietary factors,emerges as a key player.Nutrition during the first 1000 days of life shapes the gut microbiota composition,influencing immune responses and impacting both child development and adult health.High-fat,high-sugar diets can disrupt this delicate balance,contributing to inflammation and immune dysfunction.Exploring nutritional strategies,the Mediterranean diet's anti-inflammatory and antioxidant properties show promise in reducing Parkinson's disease risk.Microbiome-targeted dietary approaches and the ketogenic diet hold the potential in improving brain disorders.Beyond nutrition,emerging research uncovers potential interactions between steroid hormones,nutrition,and Parkinson's disease.Progesterone,with its anti-inflammatory properties and presence in the nervous system,offers a novel option for Parkinson's disease therapy.Its ability to enhance neuroprotection within the enteric nervous system presents exciting prospects.The review addresses the hypothesis thatα-synuclein aggregates originate from the gut and may enter the brain via the vagus nerve.Gastrointestinal symptoms preceding motor symptoms support this hypothesis.Dysfunctional gut-brain signaling during gut dysbiosis contributes to inflammation and neurotransmitter imbalances,emphasizing the potential of microbiota-based interventions.In summary,this review uncovers the complex web of interactions between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the gut-brain axis framework.Understanding these connections not only offers novel therapeutic insights but also illuminates the origins of neurodegenerative diseases such as Parkinson's disease.展开更多
Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of t...Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive.Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease.Notably,several of these genes are linked to the synaptic vesicle recycling process,particularly the clathrinmediated endocytosis pathway.This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease,followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a"dying back"mechanism.Recently,several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized.These models faithfully recapitulate certain Parkinson's disease-like features at the animal,circuit,and cellular levels,and exhibit defects in synaptic membrane trafficking,further supporting the findings from human genetics and clinical studies.In this review,we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins:auxilin(DNAJC6/PARK19)and synaptojanin 1(SYNJ1/PARK20).The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect.Subsequently,we will delve into the involvement of several clathrin-mediated endocytosis-related proteins(GAK,endophilin A1,SAC2/INPP5 F,synaptotagmin-11),identified as Parkinson's disease risk factors through genome-wide association studies,in Parkinson's disease pathogenesis.We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins(alpha-synuclein(PARK1/4),Parkin(PARK2),and LRRK2(PARK8))in synaptic endocytic trafficking.Additionally,we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways,particularly autophagy.Given that synaptic dysfunction is considered as an early event in Parkinson's disease,a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel to rgets for early diagnosis and the development of interventional therapies for Parkinson's disease.Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.展开更多
Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucia...Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucial mitochondrial protein,has been reported to cause Parkinson's disease.FIFO-ATPase participates in the synthesis of cellular adenosine triphosphate(ATP)and plays a central role in mitochondrial energy metabolism.However,the specific roles of wild-type(WT)CHCHD2 and T611-mutant CHCHD2 in regulating F1FO-ATPase activity in Parkinson's disease,as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1FO-ATPase activity,remain unclea r.Therefore,in this study,we expressed WT CHCHD2 and T61l-mutant CHCHD2 in an MPP^(+)-induced SH-SY5Y cell model of PD.We found that CHCHD2 protected mitochondria from developing MPP^(+)-induced dysfunction.Under normal conditions,ove rexpression of WT CHCHD2 promoted F1FO-ATPase assembly,while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1FO-ATPase assembly.In addition,mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1FO-ATPase.Three weeks after transfection with AAV-CHCHD2 T61I,we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson's disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model.These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.展开更多
Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatme...Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatments may help treat Parkinson's disease.To further investigate the mechanisms of action of these two compounds,we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin.We found that both exendin-4 and linagliptin reversed motor dysfunction,glial activation,and dopaminergic neuronal death in this model.In addition,both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion.Moreover,in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain-and leucine-rich-repeat-and pyrin-domaincontaining 3/caspase-1/interleukin-1βpathway and subsequent pyroptosis by decreasing the production of reactive oxygen species.These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotidebinding oligomerization domain-and leucine-rich-repeat-and pyrin-domain-containing 3/caspase-1/interleukin-1βpathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Therefore,these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.展开更多
This critical review of the literature shows that there is a close link between the microbiome,the gut,and the brain in Parkinson's disease.The vagus nerve,the main component of the parasympathetic nervous system,...This critical review of the literature shows that there is a close link between the microbiome,the gut,and the brain in Parkinson's disease.The vagus nerve,the main component of the parasympathetic nervous system,is involved in the regulation of immune response,digestion,heart rate,and control of mood.It can detect microbiota metabolites through its afferents,transferring this gut information to the central nervous system.Preclinical and clinical studies have shown the important role played by the gut microbiome and gut-related factors in disease development and progression,as well as treatment responses.These findings suggest that the gut microbiome may be a valuable target for new therapeutic strategies for Parkinson's disease.More studies are needed to better understand the underlying biology and how this axis can be modulated for the patient's benefit.展开更多
AIM: To observe the changes in the thickness of peripapillary retinal nerve fiber layer(p RNFL) and peripapillary vessel density(pVD) in patients with different stages of Parkinson's disease(PD).METHODS: Totally 4...AIM: To observe the changes in the thickness of peripapillary retinal nerve fiber layer(p RNFL) and peripapillary vessel density(pVD) in patients with different stages of Parkinson's disease(PD).METHODS: Totally 47 patients(47 eyes) with primary PD were divided into the mild group and the moderateto-severe group according to Hoehn & Yahr(H&Y) stage. Among them, there were 27 cases(27 eyes) in mild group and 20 cases(20 eyes) in moderate-to-severe group. And 20 cases(20 eyes) who were included in the control group were healthy people who came to our hospital for health screening at the same time. All participants underwent optical coherence tomography angiography(OCTA) examinations. The pRNFL thickness, total vessel density(tVD) and capillary vessel density(cVD) of the optic disc in average, superior half, inferior half, superior nasal(SN), nasal superior(NS), nasal inferior(NI), inferior nasal(IN), inferior temporal(IT), temporal inferior(TI), temporal superior(TS), and superior temporal(ST) were measured. One-way ANOVA was used to compare the differences of optic disc parameters among the three groups, and Pearson and Spearman correlations were used to analyze the correlation between pRNFL, pVD and the disease duration, H&Y stage and UPDRS-Ⅲ score in patients with PD, respectively.RESULTS: There were significant differences in p RNFL thickness in average, superior half, inferior half, SN, NS, IN, IT and ST quadrants among the three groups(P<0.05). In PD group, the pRNFL thickness in average, superior half, inferior half, NS and IT quadrants were negatively correlated with H&Y stage and UPDRS-Ⅲ score, respectively(P<0.05). There were statistically significant differences in the cVD of whole image, inferior half, NI and TS quadrants, the tVD of the whole image, inferior half, and peripapillary among the three groups(P<0.05). In PD group, the tVD of whole image and the c VD of NI and TS quadrants were negatively correlated with the H&Y stage, respectively(P<0.05);the cVD of TS quadrant was negatively correlated with UPDRS-Ⅲ score(P<0.05).CONCLUSION: The thickness of pRNFL in PD patients is significantly decreased, and it is negatively correlated with H&Y stage and UPDRS-Ⅲ score. With the increase of the severity of the disease, the pVD parameters in PD patients increase at first in the mild group, and then decrease in the moderate-to-severe group, and negatively correlate with H&Y stage and UPDRS-Ⅲ score.展开更多
The transient receptor potential melastatin 2 is a calcium-permeable cation channel member of the TRP family. Also known as an oxidative stress-activated channel, the transient receptor potential melastatin 2 gating m...The transient receptor potential melastatin 2 is a calcium-permeable cation channel member of the TRP family. Also known as an oxidative stress-activated channel, the transient receptor potential melastatin 2 gating mechanism is dependent on reactive oxygen species. In pathological conditions, transient receptor potential melastatin 2 is overactivated, leading to a Ca~(2+) influx that alters cell homeostasis and promotes cell death. The role of transient receptor potential melastatin 2 in neurodegenerative diseases, including Alzheimer's disease and ischemia, has already been described and reviewed. However, data on transient receptor potential melastatin 2 involvement in Parkinson's disease pathology has emerged only in recent years and the issue lacks review studies that focus specifically on this topic. The present review aims to elucidate the role of the transient receptor potential melastatin 2 channel in Parkinson's disease by reviewing, summarizing, and discussing the in vitro, in vivo, and human studies published until August 2022. Here we describe fourteen studies that evaluated the transient receptor potential melastatin 2 channel in Parkinson's disease. The Parkinson's disease model used, transient receptor potential melastatin 2 antagonist and genetic approaches, and the main outcomes reported were discussed. The studies described transient receptor potential melastatin 2 activation and enhanced expression in different Parkinson's disease models. They also evidenced protective and restorative effects when using transient receptor potential melastatin 2 antagonists, knockout, or silencing. This review provides a literature overview and suggests where there is a need for more research. As a perspective point, this review shows evidence that supports transient receptor potential melastatin 2 as a pharmacological target for Parkinson's disease in the future.展开更多
By controlling the proper folding of proteins imported into mitochondria and ensuring crosstalk between the reticulum and mitochondria to modulate intra cellular calcium fluxes.Mortalin is a chaperone protein that pla...By controlling the proper folding of proteins imported into mitochondria and ensuring crosstalk between the reticulum and mitochondria to modulate intra cellular calcium fluxes.Mortalin is a chaperone protein that plays crucial roles in neuronal homeostasis and activity.Howeve r,its expression and stability are strongly modified in response to cellular stresses,in particular upon alte red oxidative conditions during neurodegeneration.Here,we report and discuss the abundant literature that has highlighted its contribution to the pathophysiology of Parkinson's disease,as well as its therapeutic and prognostic potential in this still incurable pathology.展开更多
Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease(PD).However,the mechanisms underlying this association remain unclear.In the present study,we found ...Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease(PD).However,the mechanisms underlying this association remain unclear.In the present study,we found that high glucose(HG)levels in the cerebrospinal fluid(CSF)of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine(6-OHDA)on the development of motor disorders,and the damage to the nigrostriatal dopaminergic neuronal pathway.In vitro,HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor(NGF)(NGF-PC12).Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle(TCA cycle)activity,which was closely related to abnormal mitochondrial fusion,thus resulting in mitochondrial loss.Interestingly,HG-induced upregulation of pyruvate kinase M2(PKM2)combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells.In addition,we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HGþ6-OHDA.Furthermore,we found that shikonin(SK),an inhibitor of PKM2,restored the mitochondrial number,promoted TCA cycle activity,reversed hyperglycolysis,enhanced the tolerance of cultured neurons to 6-OHDA,and reduced the risk of PD in diabetic rats.Overall,our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2,leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA.Thus,the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.展开更多
It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease(PD).Dioscin,a bioactive steroidal saponin,shows various activities.However,its effect...It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease(PD).Dioscin,a bioactive steroidal saponin,shows various activities.However,its effects and mechanisms against PD are limited.In this study,dioscin dramatically alleviated neuroinflammation and oxidative stress,and restored the disorders of mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).16 S rDNA sequencing assay demonstrated that dioscin reversed MPTP-induced gut dysbiosis to decrease Firmicutes-to-Bacteroidetes ratio and the abundances of Enterococcus,Streptococcus,Bacteroides and Lactobacillus genera,which further inhibited bile salt hydrolase(BSH)activity and blocked bile acid(BA)deconjugation.Fecal microbiome transplantation test showed that the anti-PD effect of dioscin was gut microbiota-dependent.In addition,non-targeted fecal metabolomics assays revealed many differential metabolites in adjusting steroid biosynthesis and primary bile acid biosynthesis.Moreover,targeted bile acid metabolomics assay indicated that dioscin increased the levels of ursodeoxycholic acid,tauroursodeoxycholic acid,taurodeoxycholic acid and bmuricholic acid in feces and serum.In addition,ursodeoxycholic acid administration markedly improved the protective effects of dioscin against PD in mice.Mechanistic test indicated that dioscin significantly up-regulated the levels of takeda G protein-coupled receptor 5(TGR5),glucagon-like peptide-1 receptor(GLP-1R),GLP-1,superoxide dismutase(SOD),and down-regulated NADPH oxidases 2(NOX2)and nuclear factor-kappaB(NF-kB)levels.Our data indicated that dioscin ameliorated PD phenotype by restoring gut dysbiosis and regulating bile acid-mediated oxidative stress and neuroinflammation via targeting GLP-1 signal in MPTP-induced PD mice,suggesting that the compound should be considered as a prebiotic agent to treat PD in the future.展开更多
Objective:To explore the intervention mechanism of Thymoquinone in regulating NLR Family Pyrin Domain Containing 3(NLRP3)inflammasome mediated on neuroinflammatory injury of dopaminergic neurons in Parkinson's dis...Objective:To explore the intervention mechanism of Thymoquinone in regulating NLR Family Pyrin Domain Containing 3(NLRP3)inflammasome mediated on neuroinflammatory injury of dopaminergic neurons in Parkinson's disease.Methods:After establishment of the MPTP-induced PD mouse model,which was randomly divided into control group,control+TQ group,model group and model+TQ group.The effects of TQ on the motor deficits in PD mice were evaluated by open-field test and rotarod test.The effects of TQ on the expression of tyrosine hydroxylase,α-Synuclein and NLRP3 inflammasomes in midbrain of PD mice were determined by Western blot.In vivo,BV-2 cells were induced by lipopolysaccharide+and MPP to establish neuroinflammation models of Parkinson's disease.The cell supernatant was collected as conditioned medium and acted on human neuroblastoma(SH-SY5Y)cells to construct PD inflammatory injury model.MTT method determined the optimal concentration+of TQ and MPP in vitro intervention and the survival rate of cells in each intervention group;SH-SY5Y cells apoptosis was detected by TUNEL.Western blot was used to analyze the expression of Bax,Bcl-2,Caspase-3 proteins in each experimental group.The effect of TQ on the proinflammatory factor interleukin 1βby ELISA.The expression of related proteins NLRP3,ASC,Caspase-1,IL-1βand Tubulin were detected by Western blot after TQ treatment.Results:Compared with normal group,the motor function of model group was significantly decreased(P<0.01),the motor function of TQ group was significantly increased(P<0.01).In Western blot experiment,compared with normal group,theα-Syn level in model group was significantly increased(P<0.01).Compared with model group,TQ significantly decreased theα-Syn level of MPTP mice(P<0.01);Compared with model group,TH protein expression was significantly increased after TQ administration(P<0.01).TQ further inhibited the up-regulation of NLRP3,Caspase-1,IL-1β,ASC protein expression in PD mice(P<0.01).MTT detection found that the survival rate of SH-SY5Y cells after-1+100μmol∙L MPP treatment was significantly decreased,SH-SY5Y cells damage can be+relieved after TQ treatment.TUNEL staining showed that SH-SY5Y cells treated with MPP conditioned medium could induce apoptosis,and TQ pretreatment could significantly(P<0.01)reduce the apoptosis rate.Western blotting showed that MPP+conditioned medium caused the down regulation of Bcl-2/Bax in SH-SY5Y cells,while TQ inhibited the down regulation+of Bcl-2/Bax.Meanwhile,MPP conditioned medium induced the activation of Caspase-3 in SH-SY5Y cells,and caspase-3 expression was decreased by TQ(P<0.01).ELISA kit showed+that TQ inhibited MPP induced IL-1βcontent increases(P<0.01).Western blotting showed that TQ inhibited the protein expression of NLRP3,Caspase-1,IL-1βand ASC of BV-2 cells+induced by MPP(P<0.01).Conclusion:Thymoquinone can reduce the inflammatory damage of PD model neurons by inhibiting the activation of NLRP3 inflammasome in PD model,and thus play a protective role in dopaminergic neurons.展开更多
Objective:To explore the improving effect of verbascoside on Parkinson's disease(PD)model mice and to clarify the possible mechanism.Methods:60 C57BL/6 male mice were randomly divided into normal group,model group...Objective:To explore the improving effect of verbascoside on Parkinson's disease(PD)model mice and to clarify the possible mechanism.Methods:60 C57BL/6 male mice were randomly divided into normal group,model group,low,middle and high dose groups(30,60 and 120 mg/kg,respectively).After a week of adaptive culture,except for the blank group,the subacute model of PD was established by intraperitoneal injection of 1-methyl-4-phenyl-1(MPTP)in each group for 5 consecutive days.After a week of adaptive culture,except for the blank group,the subacute model of PD was established by intraperitoneal injection of 1-methyl-4-phenyl-1(MPTP)in each group for 5 consecutive days.The establishment of the model,the drug group was intragastrically administered continuously for 7 d,and the mice in the normal group were injected with the same amount of saline.The behavioral changes of mice were observed by open field test,pole climbing test and grip test;the morphology,apoptosis and Nissl bodies of substantia nigra neurons were observed by HE staining and Nissl staining;the ultrastructural changes of neurons were observed by transmission electron microscope;the positive expressions of tyrosine hydroxylase(TH),α-synuclein(α-Syn)and toll-like receptor 4(TLR4)were detected by immunohistochemistry.The protein levels of TH,α-Syn,TLR4,NF-κB and P-NF-κB in substantia nigra of mice were detected by Western blot,and the levels of inflammatory factors IL-1β,IL-6 and tumor necrosis factor-α(TNF-α)in serum were detected by Elisa.Molecular docking was used to verify the binding ability of verbascoside to TLR4/NF-κB signal pathway and related factors,and molecular dynamics was used to verify the binding mode and stability of verbascoside with compounds.Results:compared with the normal group,the total walking distance,average speed,free activity time,pole climbing time and forelimb grip in the model group were significantly longer than those in the normal group(P<0.05).The ultrastructural changes of neurons,nuclear lysis,deformation and mitochondrial damage were observed under transmission electron microscope,and the number and morphological changes of HE staining substantia nigra neurons were decreased(P<0.05).Nissl staining showed that the number of Nissl positive cells decreased(P<0.05),the positive expression of TH decreased and the positive expression of α-syn and TLR4 increased(P<0.05).Western blotting showed that the expression of TH protein decreased,the expression of α-syn,TLR4,NF-κB p65 protein increased(P<0.05),and the expression of IL-1β,IL-6 and TNF-α in serum increased significantly(P<0.05).Compared with the model group,the activity ability of mice in the treatment group was significantly improved(P<0.05),the morphology of neurons gradually recovered and the number of neurons increased(P<0.05).The number of Nissl positive cells increased(P<0.05).The expression of TH protein increased,while the expression of α-syn,TLR4,NF-κBp65 protein decreased(P<0.05),and the expression of IL-1β,IL-6,TNF-α in serum decreased significantly(P<0.05).The results of molecular docking and molecular dynamics simulation show that the combination of mulberry glycoside with the compound is good and the property is stable.Conclusion:verbascoside has protective effect on PD mice,and its mechanism may be related to TLR4/NF-κB pathway,and then regulate neuroimmunity.展开更多
Parkinson's disease(PD)is a chronic progressive neurodegenerative disease.Deep brain stimulation(DBS)is an effective treatment for patients with advanced PD.There are many DBS targets for PD,including subthalamic ...Parkinson's disease(PD)is a chronic progressive neurodegenerative disease.Deep brain stimulation(DBS)is an effective treatment for patients with advanced PD.There are many DBS targets for PD,including subthalamic nucleus(STN),globus pallidus(GPi),meso-ventral thalamic nucleus(VIM),pontine peduncle nucleus(PPN),posterior subthalamic region(PSA)and zonation of undetermined zone(ZI).This paper summarizes the efficacy of each target in the treatment of PD with DBS,not only makes a systematic analysis and comparison of motor symptoms,but also makes a detailed description of the efficacy of non-motor symptoms,so as to provide a personalized treatment basis for PD patients to select appropriate target targets in DBS.展开更多
Objective:To evaluate the effect of lycopene on Parkinson's disease cell model and its possible mechanism.Methods:The SH-SY5Y cells were treated with 0.5μmol/L rotenone for 24 h to establish Parkinson's disea...Objective:To evaluate the effect of lycopene on Parkinson's disease cell model and its possible mechanism.Methods:The SH-SY5Y cells were treated with 0.5μmol/L rotenone for 24 h to establish Parkinson's disease cell model.The experiments were randomly divided into the control group,the lycopene group,the rotenone group,the pretreatment groups of different concentrations lycopene(low,medium,high concentration).Cell viability was detected by CCK-8 assay,the morphological changes of cells were observed under an inverted microscope,Hoechst staining was used to observe cell apoptosis,the expression and distribution of endoplasmic reticulum stress marker proteins GRP78 and CHOP in each group were detected by Western blot and cell immunofluorescence.Results:The study found that compared with the control group,the cell viability in the rotenone group was significantly decreased with obvious apoptosis;compared with the rotenone group,the cell viability of the lycopene pretreatment group was improved,and the difference was statistically significant(P<0.05);The apoptosis in the lycopene pretreatment group was decreased.The expression of GRP78 and CHOP in the rotenone group was significantly higher than that in the control group(P<0.01),while the expression of both in the high concentration lycopene pretreatment group was lower than that in the rotenone group(P<0.05).Conclusion:Lycopene pretreatment had a significant protective effect on rotenone-induced SH-SY5Y cells,which may be related to the fact that lycopene pretreatment can effectively alleviate endoplasmic reticulum stress in SH-SY5Y cells damaged by rotenone.展开更多
Amide proton transfer (APT) magnetic resonance imaging (MRI) is an important molecularimaging technique at the protein level in tissue. Neurodegenerative diseases have a highlikelihood of causing abnormal protein accu...Amide proton transfer (APT) magnetic resonance imaging (MRI) is an important molecularimaging technique at the protein level in tissue. Neurodegenerative diseases have a highlikelihood of causing abnormal protein accumulation in the brain, which can be detectedby APT MRI. This article briefly introduces the principles and image processing technologyof APT MRI, and reviews the current state of research on Alzheimer's disease and Parkinson's disease using this technique. Early applications of this approach in these twoneurodegenerative diseases are encouraging, which also suggests continued technicaldevelopment and larger clinical trials to gauge the value of this technique.展开更多
Objective:To explore the clinical characteristics and analyze the influencing factors of depression and cognitive impairment in Parkinson's patients.Methods:127 patients with Parkinson's disease who were treat...Objective:To explore the clinical characteristics and analyze the influencing factors of depression and cognitive impairment in Parkinson's patients.Methods:127 patients with Parkinson's disease who were treated in two hospitals from March 2021 to March 2023 were selected for this study.The assessment of depression was conducted using the Geriatric Depression Self-Rating Scale(GDS).In addition,cognitive function was evaluated through the Montreal Cognitive Assessment(MOCA),and the clinical attributes of patients with cognitive impairment were examined.The study also aimed to analyze the factors that influence cognitive impairment in this patient population.Results:The progression of the disease,presence of cognitive impairment,and the Hoehn-Yahr stage were identified as significant influencing factors for depression among the 127 patients with Parkinson's disease(P<0.05).The factors that influence cognitive impairment included the level of education,Hoehn-Yahr stage,and depression(P<0.05).Conclusion:Depression and cognitive dysfunction is relatively common in patients with Parkinson's disease.The occurrence of depression and cognitive dysfunction varies significantly based on factors such as the duration of the disease,varying drug dosages,and the severity of the condition.Therefore,it is necessary to treat patients with Parkinson's disease.展开更多
BACKGROUND Constipation is one of the most important nonmotor symptoms in Parkinson's disease(PD)patients,and constipation of different severities is closely related to the pathogenesis of PD.PD with constipation(...BACKGROUND Constipation is one of the most important nonmotor symptoms in Parkinson's disease(PD)patients,and constipation of different severities is closely related to the pathogenesis of PD.PD with constipation(PDC)is considered a unique type of constipation,but its mechanism of formation and factors affecting its severity have been less reported.Understanding the gastrointestinal motility characteristics and constipation classification of PDC patients is essential to guide the treatment of PDC.In this study,the colonic transit test and high-resolution anorectal manometry were used to identify the intestinal motility of PDC to provide a basis for the treatment of PDC.AIM To investigate the clinical classification of PDC,to clarify its characteristics of colonic motility and rectal anal canal pressure,and to provide a basis for further research on the pathogenesis of PDC.METHODS Twenty PDC patients and 20 patients with functional constipation(FC)who were treated at Xuanwu Hospital of Capital Medical University from August 6,2018 to December 2,2019 were included.A colonic transit test and high-resolution anorectal manometry were performed to compare the differences in colonic transit time,rectal anal canal pressure,and constipation classification between the two groups.RESULTS There were no statistically significant differences in sex,age,body mass index,or duration of constipation between the two groups.It was found that more patients in the PDC group exhibited difficulty in defecating than in the FC group,and the difference was statistically significant.The rectal resting pressure,anal sphincter resting pressure,intrarectal pressure,and anal relaxation rate in the PDC group were significantly lower than those in the FC group.The proportion of paradoxical contractions in the PDC group was significantly higher than that in the FC group.There was a statistically significant difference in the type composition ratio of defecatory disorders between the two groups(P<0.05).The left colonic transit time,rectosigmoid colonic transit time(RSCTT),and total colonic transit time were prolonged in PDC and FC patients compared to normal values.The patients with FC had a significantly longer right colonic transit time and a significantly shorter RSCTT than patients with PDC(P<0.05).Mixed constipation predominated in PDC patients and FC patients,and no significant difference was observed.CONCLUSION Patients with PDC and FC have severe functional dysmotility of the colon and rectum,but there are certain differences in segmental colonic transit time and rectal anal canal pressure between the two groups.展开更多
Parkinson's disease(PD) can be classified into three motor-based subtypes: postural instability/gait difficulty(PIGD), tremor dominant(TD), and indeterminate.The neuropathophysiological mechanisms of the three mot...Parkinson's disease(PD) can be classified into three motor-based subtypes: postural instability/gait difficulty(PIGD), tremor dominant(TD), and indeterminate.The neuropathophysiological mechanisms of the three motor subtypes are different, which may lead to different responses to therapy.Sixty-nine patients with idiopathic Parkinson's disease(Hoehn–Yahr stage ≤ 3) were screened from 436 patients with Parkinsonism recruited through outpatient services and the internet.According to the Movement Disorder Society Unified Parkinson's Disease Rating Scale(MDS-UPDRS) TD/PIGD ratio, the patients were divided into PIGD(TD/PIGD ≤ 0.09;n = 36), TD(TD/PIGD ≥1.15;n = 19), and indeterminate(TD/PIGD = 0.90–1.15;n = 14) groups.All patients received 2 weeks of multidisciplinary intensive rehabilitation treatment(MIRT) during hospitalization, as well as a remote home rehabilitation health education class.Compared with the scores at admission, all patients showed significant improvements in their MDS-UPDRS III score, walking ability, balance, and posture control at discharge.Moreover, the MDS-UPDRS III score improvement was greater in the PIGD group than in the TD group.The follow-up data, collected for 3 months after discharge, showed that overall symptom improvement in each group was maintained for 1–3 months.Furthermore, there were no significant differences in the duration or grade effects of symptom improvement among the three groups.These findings suggest that 2 weeks of MIRT is effective for improving motor performance in all three motor subtypes.Patients in the PIGD group had a better response after hospitalization than those in the TD group.This study was approved by the Institutional Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University of China(approval No.2018 bkky022) on May 7, 2018 and registered with the Chinese Clinical Trial Registry(registration No.Chi CTR1900020771) on January 19, 2019.展开更多
文摘The search fo r reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis,to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies.Despite the need for non-invasively accessible biomarke rs,the majo rity of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers,which require invasive collection procedures.Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers.In the present study,after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease,we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients.A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289articles.After screening and exclusion,34 relevant articles were derived fo r systematic review.Alpha-synuclein,the histopathological hallmark of Parkinson's disease,has been the most investigated Parkinson's disease biomarker in saliva,with oligomeric alphasynuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls,while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein,and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease.Beyond alpha-synuclein,other biomarkers to rgeting diffe rent molecular pathways have been explored in the saliva of Parkinson's disease patients:total tau,phosphorylated tau,amyloid-β1-42(pathological protein aggregation biomarkers);DJ-1,heme-oxygenase-l,metabolites(alte red energy homeostasis biomarkers);MAPLC-3beta(aberrant proteostasis biomarker);cortisol,tumor necrosis factor-alpha(inflammation biomarkers);DNA methylation,miRNA(DNA/RNA defects biomarkers);acetylcholinesterase activity(synaptic and neuronal network dysfunction biomarkers);Raman spectra,proteome,and caffeine.Despite a few studies investigating biomarkers to rgeting molecular pathways different from alpha-synuclein in Parkinson's disease,these results should be replicated and observed in studies on larger cohorts,considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes.Although the need fo r standardization in sample collection and processing,salivary-based biomarkers studies have reported encouraging results,calling for large-scale longitudinal studies and multicentric assessments,given the great molecular potentials and the non-invasive accessibility of saliva.
文摘This comprehensive review explores the intricate relationship between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the context of the gut-brain axis.The gut-brain axis plays a pivotal role in neurodegenerative diseases like Parkinson's disease,encompassing diverse components such as the gut microbiota,immune system,metabolism,and neural pathways.The gut microbiome,profoundly influenced by dietary factors,emerges as a key player.Nutrition during the first 1000 days of life shapes the gut microbiota composition,influencing immune responses and impacting both child development and adult health.High-fat,high-sugar diets can disrupt this delicate balance,contributing to inflammation and immune dysfunction.Exploring nutritional strategies,the Mediterranean diet's anti-inflammatory and antioxidant properties show promise in reducing Parkinson's disease risk.Microbiome-targeted dietary approaches and the ketogenic diet hold the potential in improving brain disorders.Beyond nutrition,emerging research uncovers potential interactions between steroid hormones,nutrition,and Parkinson's disease.Progesterone,with its anti-inflammatory properties and presence in the nervous system,offers a novel option for Parkinson's disease therapy.Its ability to enhance neuroprotection within the enteric nervous system presents exciting prospects.The review addresses the hypothesis thatα-synuclein aggregates originate from the gut and may enter the brain via the vagus nerve.Gastrointestinal symptoms preceding motor symptoms support this hypothesis.Dysfunctional gut-brain signaling during gut dysbiosis contributes to inflammation and neurotransmitter imbalances,emphasizing the potential of microbiota-based interventions.In summary,this review uncovers the complex web of interactions between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the gut-brain axis framework.Understanding these connections not only offers novel therapeutic insights but also illuminates the origins of neurodegenerative diseases such as Parkinson's disease.
文摘Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive.Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease.Notably,several of these genes are linked to the synaptic vesicle recycling process,particularly the clathrinmediated endocytosis pathway.This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease,followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a"dying back"mechanism.Recently,several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized.These models faithfully recapitulate certain Parkinson's disease-like features at the animal,circuit,and cellular levels,and exhibit defects in synaptic membrane trafficking,further supporting the findings from human genetics and clinical studies.In this review,we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins:auxilin(DNAJC6/PARK19)and synaptojanin 1(SYNJ1/PARK20).The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect.Subsequently,we will delve into the involvement of several clathrin-mediated endocytosis-related proteins(GAK,endophilin A1,SAC2/INPP5 F,synaptotagmin-11),identified as Parkinson's disease risk factors through genome-wide association studies,in Parkinson's disease pathogenesis.We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins(alpha-synuclein(PARK1/4),Parkin(PARK2),and LRRK2(PARK8))in synaptic endocytic trafficking.Additionally,we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways,particularly autophagy.Given that synaptic dysfunction is considered as an early event in Parkinson's disease,a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel to rgets for early diagnosis and the development of interventional therapies for Parkinson's disease.Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.
基金supported by the National Natural Science Foundation of China(Youth Program),No.81901282(to XC)the National Natural Science Foundation of China,Nos.81401416(to PX),81870992(to PX),81870856(to XC and MZ)+3 种基金Guangdong Basic and Applied Basic Research Foundation the Science Foundation,No.2019A1515011189(to XC)Central Government Guiding Local Science and Technology Development Projects,No.ZYYD2022C17(to PX)Key Project of Guangzhou Health Commission,No.2019-ZD-09(to PX)Science and Technology Planning Project of Guangzhou,Nos.202102020029(to XC),202102010010(to PX)。
文摘Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucial mitochondrial protein,has been reported to cause Parkinson's disease.FIFO-ATPase participates in the synthesis of cellular adenosine triphosphate(ATP)and plays a central role in mitochondrial energy metabolism.However,the specific roles of wild-type(WT)CHCHD2 and T611-mutant CHCHD2 in regulating F1FO-ATPase activity in Parkinson's disease,as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1FO-ATPase activity,remain unclea r.Therefore,in this study,we expressed WT CHCHD2 and T61l-mutant CHCHD2 in an MPP^(+)-induced SH-SY5Y cell model of PD.We found that CHCHD2 protected mitochondria from developing MPP^(+)-induced dysfunction.Under normal conditions,ove rexpression of WT CHCHD2 promoted F1FO-ATPase assembly,while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1FO-ATPase assembly.In addition,mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1FO-ATPase.Three weeks after transfection with AAV-CHCHD2 T61I,we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson's disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model.These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.
基金supported by the National Natural Science Foundation of China,Nos.81771271(to JF),31800898(to WL),81430025(to JYL),and U1801681(to JYL)Key Research and Development Program of Liaoning Province,No.2020JH2/10300047(to JF)+1 种基金the Key Field Research Development Program of Guangdong Province,No.2018B030337001(to JYL)the Outstanding Scientific Fund of Shengjing Hospital,No.M0475(to JF)。
文摘Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatments may help treat Parkinson's disease.To further investigate the mechanisms of action of these two compounds,we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin.We found that both exendin-4 and linagliptin reversed motor dysfunction,glial activation,and dopaminergic neuronal death in this model.In addition,both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion.Moreover,in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain-and leucine-rich-repeat-and pyrin-domaincontaining 3/caspase-1/interleukin-1βpathway and subsequent pyroptosis by decreasing the production of reactive oxygen species.These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotidebinding oligomerization domain-and leucine-rich-repeat-and pyrin-domain-containing 3/caspase-1/interleukin-1βpathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Therefore,these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.
基金Medical School of the Christus University Center(UNICHRISTUS)Federal University of Ceará(UFC)Fundacao de AmparoàPesquisa do Estado de S?o Paulo(FAPESP,grants 2021/06473-4)(to JCCS)。
文摘This critical review of the literature shows that there is a close link between the microbiome,the gut,and the brain in Parkinson's disease.The vagus nerve,the main component of the parasympathetic nervous system,is involved in the regulation of immune response,digestion,heart rate,and control of mood.It can detect microbiota metabolites through its afferents,transferring this gut information to the central nervous system.Preclinical and clinical studies have shown the important role played by the gut microbiome and gut-related factors in disease development and progression,as well as treatment responses.These findings suggest that the gut microbiome may be a valuable target for new therapeutic strategies for Parkinson's disease.More studies are needed to better understand the underlying biology and how this axis can be modulated for the patient's benefit.
文摘AIM: To observe the changes in the thickness of peripapillary retinal nerve fiber layer(p RNFL) and peripapillary vessel density(pVD) in patients with different stages of Parkinson's disease(PD).METHODS: Totally 47 patients(47 eyes) with primary PD were divided into the mild group and the moderateto-severe group according to Hoehn & Yahr(H&Y) stage. Among them, there were 27 cases(27 eyes) in mild group and 20 cases(20 eyes) in moderate-to-severe group. And 20 cases(20 eyes) who were included in the control group were healthy people who came to our hospital for health screening at the same time. All participants underwent optical coherence tomography angiography(OCTA) examinations. The pRNFL thickness, total vessel density(tVD) and capillary vessel density(cVD) of the optic disc in average, superior half, inferior half, superior nasal(SN), nasal superior(NS), nasal inferior(NI), inferior nasal(IN), inferior temporal(IT), temporal inferior(TI), temporal superior(TS), and superior temporal(ST) were measured. One-way ANOVA was used to compare the differences of optic disc parameters among the three groups, and Pearson and Spearman correlations were used to analyze the correlation between pRNFL, pVD and the disease duration, H&Y stage and UPDRS-Ⅲ score in patients with PD, respectively.RESULTS: There were significant differences in p RNFL thickness in average, superior half, inferior half, SN, NS, IN, IT and ST quadrants among the three groups(P<0.05). In PD group, the pRNFL thickness in average, superior half, inferior half, NS and IT quadrants were negatively correlated with H&Y stage and UPDRS-Ⅲ score, respectively(P<0.05). There were statistically significant differences in the cVD of whole image, inferior half, NI and TS quadrants, the tVD of the whole image, inferior half, and peripapillary among the three groups(P<0.05). In PD group, the tVD of whole image and the c VD of NI and TS quadrants were negatively correlated with the H&Y stage, respectively(P<0.05);the cVD of TS quadrant was negatively correlated with UPDRS-Ⅲ score(P<0.05).CONCLUSION: The thickness of pRNFL in PD patients is significantly decreased, and it is negatively correlated with H&Y stage and UPDRS-Ⅲ score. With the increase of the severity of the disease, the pVD parameters in PD patients increase at first in the mild group, and then decrease in the moderate-to-severe group, and negatively correlate with H&Y stage and UPDRS-Ⅲ score.
基金funded by Coordination for the Improvement of Higher Education Personnel (CAPES,Brazil-Finance Code 001,to LRB)the S?o Paulo Research Foundation(FAPESP,Brazil,project#2018/07366-4)+1 种基金The National Council for Scientific and Technological Development (CNPq,Brazil,project#303006/2018-8,to LRB)a PhD fellowship from FAPESP under Grant Agreement No 2020/02109-3。
文摘The transient receptor potential melastatin 2 is a calcium-permeable cation channel member of the TRP family. Also known as an oxidative stress-activated channel, the transient receptor potential melastatin 2 gating mechanism is dependent on reactive oxygen species. In pathological conditions, transient receptor potential melastatin 2 is overactivated, leading to a Ca~(2+) influx that alters cell homeostasis and promotes cell death. The role of transient receptor potential melastatin 2 in neurodegenerative diseases, including Alzheimer's disease and ischemia, has already been described and reviewed. However, data on transient receptor potential melastatin 2 involvement in Parkinson's disease pathology has emerged only in recent years and the issue lacks review studies that focus specifically on this topic. The present review aims to elucidate the role of the transient receptor potential melastatin 2 channel in Parkinson's disease by reviewing, summarizing, and discussing the in vitro, in vivo, and human studies published until August 2022. Here we describe fourteen studies that evaluated the transient receptor potential melastatin 2 channel in Parkinson's disease. The Parkinson's disease model used, transient receptor potential melastatin 2 antagonist and genetic approaches, and the main outcomes reported were discussed. The studies described transient receptor potential melastatin 2 activation and enhanced expression in different Parkinson's disease models. They also evidenced protective and restorative effects when using transient receptor potential melastatin 2 antagonists, knockout, or silencing. This review provides a literature overview and suggests where there is a need for more research. As a perspective point, this review shows evidence that supports transient receptor potential melastatin 2 as a pharmacological target for Parkinson's disease in the future.
文摘By controlling the proper folding of proteins imported into mitochondria and ensuring crosstalk between the reticulum and mitochondria to modulate intra cellular calcium fluxes.Mortalin is a chaperone protein that plays crucial roles in neuronal homeostasis and activity.Howeve r,its expression and stability are strongly modified in response to cellular stresses,in particular upon alte red oxidative conditions during neurodegeneration.Here,we report and discuss the abundant literature that has highlighted its contribution to the pathophysiology of Parkinson's disease,as well as its therapeutic and prognostic potential in this still incurable pathology.
基金the National Natural Science Foundation of China(Grant Nos.:82074039 and 82204584).
文摘Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease(PD).However,the mechanisms underlying this association remain unclear.In the present study,we found that high glucose(HG)levels in the cerebrospinal fluid(CSF)of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine(6-OHDA)on the development of motor disorders,and the damage to the nigrostriatal dopaminergic neuronal pathway.In vitro,HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor(NGF)(NGF-PC12).Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle(TCA cycle)activity,which was closely related to abnormal mitochondrial fusion,thus resulting in mitochondrial loss.Interestingly,HG-induced upregulation of pyruvate kinase M2(PKM2)combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells.In addition,we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HGþ6-OHDA.Furthermore,we found that shikonin(SK),an inhibitor of PKM2,restored the mitochondrial number,promoted TCA cycle activity,reversed hyperglycolysis,enhanced the tolerance of cultured neurons to 6-OHDA,and reduced the risk of PD in diabetic rats.Overall,our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2,leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA.Thus,the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.
基金funding from the Spring City Plan:The High-Level Talent Promotion and Training Project of Kunming and the Independent Research Fund of Yunnan Characteristic Plant Extraction Laboratory(Grant No.:2022YKZY001).
文摘It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease(PD).Dioscin,a bioactive steroidal saponin,shows various activities.However,its effects and mechanisms against PD are limited.In this study,dioscin dramatically alleviated neuroinflammation and oxidative stress,and restored the disorders of mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).16 S rDNA sequencing assay demonstrated that dioscin reversed MPTP-induced gut dysbiosis to decrease Firmicutes-to-Bacteroidetes ratio and the abundances of Enterococcus,Streptococcus,Bacteroides and Lactobacillus genera,which further inhibited bile salt hydrolase(BSH)activity and blocked bile acid(BA)deconjugation.Fecal microbiome transplantation test showed that the anti-PD effect of dioscin was gut microbiota-dependent.In addition,non-targeted fecal metabolomics assays revealed many differential metabolites in adjusting steroid biosynthesis and primary bile acid biosynthesis.Moreover,targeted bile acid metabolomics assay indicated that dioscin increased the levels of ursodeoxycholic acid,tauroursodeoxycholic acid,taurodeoxycholic acid and bmuricholic acid in feces and serum.In addition,ursodeoxycholic acid administration markedly improved the protective effects of dioscin against PD in mice.Mechanistic test indicated that dioscin significantly up-regulated the levels of takeda G protein-coupled receptor 5(TGR5),glucagon-like peptide-1 receptor(GLP-1R),GLP-1,superoxide dismutase(SOD),and down-regulated NADPH oxidases 2(NOX2)and nuclear factor-kappaB(NF-kB)levels.Our data indicated that dioscin ameliorated PD phenotype by restoring gut dysbiosis and regulating bile acid-mediated oxidative stress and neuroinflammation via targeting GLP-1 signal in MPTP-induced PD mice,suggesting that the compound should be considered as a prebiotic agent to treat PD in the future.
基金Natural Science Research Project of Anhui University of Chinese Medicine(No.2020sjzd03)。
文摘Objective:To explore the intervention mechanism of Thymoquinone in regulating NLR Family Pyrin Domain Containing 3(NLRP3)inflammasome mediated on neuroinflammatory injury of dopaminergic neurons in Parkinson's disease.Methods:After establishment of the MPTP-induced PD mouse model,which was randomly divided into control group,control+TQ group,model group and model+TQ group.The effects of TQ on the motor deficits in PD mice were evaluated by open-field test and rotarod test.The effects of TQ on the expression of tyrosine hydroxylase,α-Synuclein and NLRP3 inflammasomes in midbrain of PD mice were determined by Western blot.In vivo,BV-2 cells were induced by lipopolysaccharide+and MPP to establish neuroinflammation models of Parkinson's disease.The cell supernatant was collected as conditioned medium and acted on human neuroblastoma(SH-SY5Y)cells to construct PD inflammatory injury model.MTT method determined the optimal concentration+of TQ and MPP in vitro intervention and the survival rate of cells in each intervention group;SH-SY5Y cells apoptosis was detected by TUNEL.Western blot was used to analyze the expression of Bax,Bcl-2,Caspase-3 proteins in each experimental group.The effect of TQ on the proinflammatory factor interleukin 1βby ELISA.The expression of related proteins NLRP3,ASC,Caspase-1,IL-1βand Tubulin were detected by Western blot after TQ treatment.Results:Compared with normal group,the motor function of model group was significantly decreased(P<0.01),the motor function of TQ group was significantly increased(P<0.01).In Western blot experiment,compared with normal group,theα-Syn level in model group was significantly increased(P<0.01).Compared with model group,TQ significantly decreased theα-Syn level of MPTP mice(P<0.01);Compared with model group,TH protein expression was significantly increased after TQ administration(P<0.01).TQ further inhibited the up-regulation of NLRP3,Caspase-1,IL-1β,ASC protein expression in PD mice(P<0.01).MTT detection found that the survival rate of SH-SY5Y cells after-1+100μmol∙L MPP treatment was significantly decreased,SH-SY5Y cells damage can be+relieved after TQ treatment.TUNEL staining showed that SH-SY5Y cells treated with MPP conditioned medium could induce apoptosis,and TQ pretreatment could significantly(P<0.01)reduce the apoptosis rate.Western blotting showed that MPP+conditioned medium caused the down regulation of Bcl-2/Bax in SH-SY5Y cells,while TQ inhibited the down regulation+of Bcl-2/Bax.Meanwhile,MPP conditioned medium induced the activation of Caspase-3 in SH-SY5Y cells,and caspase-3 expression was decreased by TQ(P<0.01).ELISA kit showed+that TQ inhibited MPP induced IL-1βcontent increases(P<0.01).Western blotting showed that TQ inhibited the protein expression of NLRP3,Caspase-1,IL-1βand ASC of BV-2 cells+induced by MPP(P<0.01).Conclusion:Thymoquinone can reduce the inflammatory damage of PD model neurons by inhibiting the activation of NLRP3 inflammasome in PD model,and thus play a protective role in dopaminergic neurons.
基金Special Funds for LOCAL SCIENce and Technology Development Guided by the Central Government(No.ZYD2022C17)National Natural Science Foundation of China(No.82160232)。
文摘Objective:To explore the improving effect of verbascoside on Parkinson's disease(PD)model mice and to clarify the possible mechanism.Methods:60 C57BL/6 male mice were randomly divided into normal group,model group,low,middle and high dose groups(30,60 and 120 mg/kg,respectively).After a week of adaptive culture,except for the blank group,the subacute model of PD was established by intraperitoneal injection of 1-methyl-4-phenyl-1(MPTP)in each group for 5 consecutive days.After a week of adaptive culture,except for the blank group,the subacute model of PD was established by intraperitoneal injection of 1-methyl-4-phenyl-1(MPTP)in each group for 5 consecutive days.The establishment of the model,the drug group was intragastrically administered continuously for 7 d,and the mice in the normal group were injected with the same amount of saline.The behavioral changes of mice were observed by open field test,pole climbing test and grip test;the morphology,apoptosis and Nissl bodies of substantia nigra neurons were observed by HE staining and Nissl staining;the ultrastructural changes of neurons were observed by transmission electron microscope;the positive expressions of tyrosine hydroxylase(TH),α-synuclein(α-Syn)and toll-like receptor 4(TLR4)were detected by immunohistochemistry.The protein levels of TH,α-Syn,TLR4,NF-κB and P-NF-κB in substantia nigra of mice were detected by Western blot,and the levels of inflammatory factors IL-1β,IL-6 and tumor necrosis factor-α(TNF-α)in serum were detected by Elisa.Molecular docking was used to verify the binding ability of verbascoside to TLR4/NF-κB signal pathway and related factors,and molecular dynamics was used to verify the binding mode and stability of verbascoside with compounds.Results:compared with the normal group,the total walking distance,average speed,free activity time,pole climbing time and forelimb grip in the model group were significantly longer than those in the normal group(P<0.05).The ultrastructural changes of neurons,nuclear lysis,deformation and mitochondrial damage were observed under transmission electron microscope,and the number and morphological changes of HE staining substantia nigra neurons were decreased(P<0.05).Nissl staining showed that the number of Nissl positive cells decreased(P<0.05),the positive expression of TH decreased and the positive expression of α-syn and TLR4 increased(P<0.05).Western blotting showed that the expression of TH protein decreased,the expression of α-syn,TLR4,NF-κB p65 protein increased(P<0.05),and the expression of IL-1β,IL-6 and TNF-α in serum increased significantly(P<0.05).Compared with the model group,the activity ability of mice in the treatment group was significantly improved(P<0.05),the morphology of neurons gradually recovered and the number of neurons increased(P<0.05).The number of Nissl positive cells increased(P<0.05).The expression of TH protein increased,while the expression of α-syn,TLR4,NF-κBp65 protein decreased(P<0.05),and the expression of IL-1β,IL-6,TNF-α in serum decreased significantly(P<0.05).The results of molecular docking and molecular dynamics simulation show that the combination of mulberry glycoside with the compound is good and the property is stable.Conclusion:verbascoside has protective effect on PD mice,and its mechanism may be related to TLR4/NF-κB pathway,and then regulate neuroimmunity.
基金Natural Science Foundation of Hainan Province (No.821RC682)。
文摘Parkinson's disease(PD)is a chronic progressive neurodegenerative disease.Deep brain stimulation(DBS)is an effective treatment for patients with advanced PD.There are many DBS targets for PD,including subthalamic nucleus(STN),globus pallidus(GPi),meso-ventral thalamic nucleus(VIM),pontine peduncle nucleus(PPN),posterior subthalamic region(PSA)and zonation of undetermined zone(ZI).This paper summarizes the efficacy of each target in the treatment of PD with DBS,not only makes a systematic analysis and comparison of motor symptoms,but also makes a detailed description of the efficacy of non-motor symptoms,so as to provide a personalized treatment basis for PD patients to select appropriate target targets in DBS.
基金Science and Technology Program of Guangdong Province(No.2013B060300038)Scientific Research Foundation of Guangdong Medical University(No.GDMUM2019029)。
文摘Objective:To evaluate the effect of lycopene on Parkinson's disease cell model and its possible mechanism.Methods:The SH-SY5Y cells were treated with 0.5μmol/L rotenone for 24 h to establish Parkinson's disease cell model.The experiments were randomly divided into the control group,the lycopene group,the rotenone group,the pretreatment groups of different concentrations lycopene(low,medium,high concentration).Cell viability was detected by CCK-8 assay,the morphological changes of cells were observed under an inverted microscope,Hoechst staining was used to observe cell apoptosis,the expression and distribution of endoplasmic reticulum stress marker proteins GRP78 and CHOP in each group were detected by Western blot and cell immunofluorescence.Results:The study found that compared with the control group,the cell viability in the rotenone group was significantly decreased with obvious apoptosis;compared with the rotenone group,the cell viability of the lycopene pretreatment group was improved,and the difference was statistically significant(P<0.05);The apoptosis in the lycopene pretreatment group was decreased.The expression of GRP78 and CHOP in the rotenone group was significantly higher than that in the control group(P<0.01),while the expression of both in the high concentration lycopene pretreatment group was lower than that in the rotenone group(P<0.05).Conclusion:Lycopene pretreatment had a significant protective effect on rotenone-induced SH-SY5Y cells,which may be related to the fact that lycopene pretreatment can effectively alleviate endoplasmic reticulum stress in SH-SY5Y cells damaged by rotenone.
文摘Amide proton transfer (APT) magnetic resonance imaging (MRI) is an important molecularimaging technique at the protein level in tissue. Neurodegenerative diseases have a highlikelihood of causing abnormal protein accumulation in the brain, which can be detectedby APT MRI. This article briefly introduces the principles and image processing technologyof APT MRI, and reviews the current state of research on Alzheimer's disease and Parkinson's disease using this technique. Early applications of this approach in these twoneurodegenerative diseases are encouraging, which also suggests continued technicaldevelopment and larger clinical trials to gauge the value of this technique.
文摘Objective:To explore the clinical characteristics and analyze the influencing factors of depression and cognitive impairment in Parkinson's patients.Methods:127 patients with Parkinson's disease who were treated in two hospitals from March 2021 to March 2023 were selected for this study.The assessment of depression was conducted using the Geriatric Depression Self-Rating Scale(GDS).In addition,cognitive function was evaluated through the Montreal Cognitive Assessment(MOCA),and the clinical attributes of patients with cognitive impairment were examined.The study also aimed to analyze the factors that influence cognitive impairment in this patient population.Results:The progression of the disease,presence of cognitive impairment,and the Hoehn-Yahr stage were identified as significant influencing factors for depression among the 127 patients with Parkinson's disease(P<0.05).The factors that influence cognitive impairment included the level of education,Hoehn-Yahr stage,and depression(P<0.05).Conclusion:Depression and cognitive dysfunction is relatively common in patients with Parkinson's disease.The occurrence of depression and cognitive dysfunction varies significantly based on factors such as the duration of the disease,varying drug dosages,and the severity of the condition.Therefore,it is necessary to treat patients with Parkinson's disease.
文摘BACKGROUND Constipation is one of the most important nonmotor symptoms in Parkinson's disease(PD)patients,and constipation of different severities is closely related to the pathogenesis of PD.PD with constipation(PDC)is considered a unique type of constipation,but its mechanism of formation and factors affecting its severity have been less reported.Understanding the gastrointestinal motility characteristics and constipation classification of PDC patients is essential to guide the treatment of PDC.In this study,the colonic transit test and high-resolution anorectal manometry were used to identify the intestinal motility of PDC to provide a basis for the treatment of PDC.AIM To investigate the clinical classification of PDC,to clarify its characteristics of colonic motility and rectal anal canal pressure,and to provide a basis for further research on the pathogenesis of PDC.METHODS Twenty PDC patients and 20 patients with functional constipation(FC)who were treated at Xuanwu Hospital of Capital Medical University from August 6,2018 to December 2,2019 were included.A colonic transit test and high-resolution anorectal manometry were performed to compare the differences in colonic transit time,rectal anal canal pressure,and constipation classification between the two groups.RESULTS There were no statistically significant differences in sex,age,body mass index,or duration of constipation between the two groups.It was found that more patients in the PDC group exhibited difficulty in defecating than in the FC group,and the difference was statistically significant.The rectal resting pressure,anal sphincter resting pressure,intrarectal pressure,and anal relaxation rate in the PDC group were significantly lower than those in the FC group.The proportion of paradoxical contractions in the PDC group was significantly higher than that in the FC group.There was a statistically significant difference in the type composition ratio of defecatory disorders between the two groups(P<0.05).The left colonic transit time,rectosigmoid colonic transit time(RSCTT),and total colonic transit time were prolonged in PDC and FC patients compared to normal values.The patients with FC had a significantly longer right colonic transit time and a significantly shorter RSCTT than patients with PDC(P<0.05).Mixed constipation predominated in PDC patients and FC patients,and no significant difference was observed.CONCLUSION Patients with PDC and FC have severe functional dysmotility of the colon and rectum,but there are certain differences in segmental colonic transit time and rectal anal canal pressure between the two groups.
基金supported by the National Key Research and Development Program Sub-project, No.2018 YFC0115405(to BYF)the Start-up Fund for Scientific Research Talents of Beijing Rehabilitation Hospital, Capital Medical University of China, No.2019 R-006(to ZHJ)。
文摘Parkinson's disease(PD) can be classified into three motor-based subtypes: postural instability/gait difficulty(PIGD), tremor dominant(TD), and indeterminate.The neuropathophysiological mechanisms of the three motor subtypes are different, which may lead to different responses to therapy.Sixty-nine patients with idiopathic Parkinson's disease(Hoehn–Yahr stage ≤ 3) were screened from 436 patients with Parkinsonism recruited through outpatient services and the internet.According to the Movement Disorder Society Unified Parkinson's Disease Rating Scale(MDS-UPDRS) TD/PIGD ratio, the patients were divided into PIGD(TD/PIGD ≤ 0.09;n = 36), TD(TD/PIGD ≥1.15;n = 19), and indeterminate(TD/PIGD = 0.90–1.15;n = 14) groups.All patients received 2 weeks of multidisciplinary intensive rehabilitation treatment(MIRT) during hospitalization, as well as a remote home rehabilitation health education class.Compared with the scores at admission, all patients showed significant improvements in their MDS-UPDRS III score, walking ability, balance, and posture control at discharge.Moreover, the MDS-UPDRS III score improvement was greater in the PIGD group than in the TD group.The follow-up data, collected for 3 months after discharge, showed that overall symptom improvement in each group was maintained for 1–3 months.Furthermore, there were no significant differences in the duration or grade effects of symptom improvement among the three groups.These findings suggest that 2 weeks of MIRT is effective for improving motor performance in all three motor subtypes.Patients in the PIGD group had a better response after hospitalization than those in the TD group.This study was approved by the Institutional Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University of China(approval No.2018 bkky022) on May 7, 2018 and registered with the Chinese Clinical Trial Registry(registration No.Chi CTR1900020771) on January 19, 2019.
