Unraveling the gut-brain axis:the impact of steroid hormones and nutrition on Parkinson's disease

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.

A systematic review of salivary biomarkers in Parkinson's disease

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.

Dysfunction of synaptic endocytic trafficking in Parkinson's disease

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.

Role of the globus pallidus in motor and non-motor symptoms of Parkinson's disease

The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson's disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore,bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico–striato–pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease,particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremordominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia–thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity,and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson's disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.

CHCHD2 Thr61Ile mutation impairs F1F0-ATPase assembly in in vitro and in vivo models of Parkinson's disease

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.

Research on the Establishment of a Long-Term Care System for the Elderly with Alzheimer’s Disease Under the Background of Long-Term Care Insurance: A Literature Review

With the aging of the country’s population structure,the problem of social pensions is becoming more and more serious.As for the issue of social pension,the elderly with Alzheimer’s disease are a special group,and the issue of care services for these elderly has attracted widespread attention from society.However,judging from the current level of social security provided to the elderly with dementia in the country,there is a serious imbalance between supply and demand.Therefore,this problem needs to be solved urgently and is of great significance for further improving the country’s social pension security system.Routine care is limited to hospitals and mainly focuses on the patient’s condition.Patients fail to receive comprehensive care services and the effect is not ideal.Therefore,in order to improve patients’cognitive function and quality of life,and learn from international experience,a“community-institution-home”three-dimensional linkage care model based on long-term care insurance can be established.The application of this model can effectively solve and further improve the country’s elderly care and social security system.

Effectiveness of Atorvastatin Combined with Trimetazidine in the Treatment of Coronary Heart Disease in the Elderly and Their Effect on Cardiac Function

Objective:To analyze the effect of atorvastatin combined with trimetazidine in the treatment of elderly coronary artery disease and the effect on patients’cardiac function.Methods:60 cases of elderly coronary artery disease patients were divided into 2 groups by randomization method,and all of them received conventional symptomatic treatment,while atorvastatin was added to the control group and trimetazidine was combined with atorvastatin in the observation group,and the clinical indexes were compared.Results:After treatment,the angina attack,cardiac function indexes,and inflammatory factor levels of the observation group were better than those of the control group(P<0.05),and the differences in adverse reactions between the two groups were not significant(P>0.05).Conclusion:Combined treatment of coronary heart disease in the elderly with atorvastatin and trimetazidine can positively reduce angina symptoms,improve cardiac function,and reduce inflammatory reactions,and the effect is definite.

Analysis of the Nursing Effect of Continuity of Care on Elderly Patients with Coronary Heart Disease Unstable Angina and its Impact on Quality of Life

Objective:To analyze the effect of using continuity of care for elderly patients with coronary heart disease(CHD)with unstable angina pectoris(UAP)and its impact on their quality of life.Methods:100 cases of elderly patients with CHD with UAP admitted to our hospital from March 2022 to March 2023 were selected and grouped into an observation group and a control group of 50 cases each according to the randomized number table method.The nursing effect and quality of life of the observation group(continuity nursing)and the control group(routine nursing)were compared.Results:The total effective rate of nursing care was 96.00%observation group and 80.00%for the control group,and the differences were significant(χ2=6.061,P<0.05).Patients in the observation group had fewer episodes(1.42±0.21)times/week and a shorter duration(5.46±0.39)min,which were better than the control group(t=3.465,2.973;P<0.05).The depression self-rating depression scale(SDS)score(42.16±6.64)and anxiety self-rating scale(SAS)score(32.26±7.35)in the observation group were lower and the quality of life was higher as compared to that of the control group(P<0.05).Conclusion:Continuous nursing care improved the nursing effect of elderly CHD with UAP patients,promoted the alleviation of UAP symptoms,improved patient mentality,and improved their quality of life.Hence,continuous nursing care possesses significant clinical application value.

Analysis of the Effectiveness of Clopidogrel Combined with Aspirin in the Treatment of Coronary Heart Disease in Community-Dwelling Elderly

Objective:To analyze the combined therapeutic effect of clopidogrel(CLO)and aspirin(ASP)on coronary heart disease(CHD)in community-dwelling elderly.Methods:Thirty elderly patients with CHD who were admitted to the Xinxin Community Health Service Station,Pangzhuang Street,Quanshan District,Xuzhou City,from November 2020 to November 2022 were selected and randomly grouped into an observation group and a control group,with 15 cases in each group.The observation group was given the combination of CLO and ASP and the reference group was given only ASP.The total effective rate and other treatment indicators between the two groups were compared.Results:The total effective rate of the observation group(93.33%)was higher than that of the reference group(60.00%)(P<0.05).The adverse drug reaction rate(13.33%)and long-term cardiovascular adverse event rate(6.67%)of the observation group were lower than those of the reference group at 46.67%and 40.00%respectively,(P<0.05).Before treatment,the two groups had no difference in the quality-of-life scores(P>0.05).After treatment,the quality-of-life scores of the observation group were higher than those of the reference group(P<0.05).Conclusion:CLO combined with ASP improved the therapeutic effect of community-dwelling elderly patients with CHD,reduced adverse reactions during medication,prevented adverse cardiovascular events,and comprehensively improved the patient’s quality of life.

Gut-microbiome-brain axis:the crosstalk between the vagus nerve,alpha-synuclein and the brain in Parkinson's disease

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.

Exendin-4 and linagliptin attenuate neuroinflammation in a mouse model of Parkinson's disease

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.

Protective effects of dioscin against Parkinson's disease via regulating bile acid metabolism through remodeling gut microbiome/GLP-1 signaling

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.

Quantitative study of peripapillary retinal nerve fiber layer thickness and peripapillary vessel density in patients with different stages of Parkinson's disease

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.

The transient receptor potential melastatin 2:a new therapeutical target for Parkinson's disease?

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.

Lactate metabolism in neurodegenerative diseases

Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.

A novelα-ketoamide reactivity-based two-photon fluorogenic probe for visualizing peroxynitrite in Parkinson's disease models

Peroxynitrite(ONOO^(-))contributes to oxidative stress and neurodegeneration in Parkinson's disease(PD).Developing a peroxynitrite probe would enable in situ visualization of the overwhelming ONOO^(-)flux and understanding of the ONOO^(-)stress-induced neuropathology of PD.Herein,a novelα-ketoamide-based fluorogenic probe(DFlu)was designed for ONOO^(-)
monitoring in multiple PD models.The results demonstrated that DFlu exhibits a fluorescence turn-on response to ONOO^(-)with high specificity and sensitivity.The efficacy of DFlu for intracellular ONOO^(-)
imaging was demonstrated systematically.The results showed that DFlu can successfully visualize endogenous and exogenous ONOO^(-)in cells derived from chemical and biochemical routes.More importantly,the two-photon excitation ability of DFlu has been well demonstrated by monitoring exogenous/endogenous ONOO^(-)production and scavenging in live zebraflsh PD models.This work provides a reliable and promising
α-ketoamide-based optical tool for identifying variations of ONOO^(-)in PD models.

Mortalin/Hspa9 involvement and therapeutic perspective in Parkinson's disease

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.

PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats

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.

Inhibitory effect of thymoquinone on neuroinflammation in Parkinson's disease model by regulating NLRP3 inflammatory bodies

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.

Mechanism of action of verbascoside in mice with Parkinson's disease based on molecular docking,molecular dynamics and in vivo experiments

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.