Parkinson's Disease Is Associated with Impaired Gut-Blood Barrier for Short-Chain Fatty Acids.

BACKGROUND: Short-chain fatty acids (SCFAs) produced by gut microbiota are reduced in feces but paradoxically increased in plasma of patients with Parkinson's disease (PD), which may stem from intestinal wall leakage. Gut function should be taken into consideration when conducting microbial-metabolite research. OBJECTIVE: The objective was to investigate synchronous changes of SCFAs in feces and plasma of patients with PD, taking constipation as a confounder to better disentangle the SCFA metabolism exclusively associated with PD. METHODS: The concentrations of fecal and plasma SCFAs in 33 healthy control subjects and 95 patients with PD were measured using liquid and gas chromatography mass spectrometry, respectively. Patients with PD were divided into patients with PD without constipation (n = 35) and patients with PD with constipation (n = 60). Gut-blood barrier (GBB) permeability was assessed by plasma/fecal ratio of SCFA concentrations and fecal α1-antitrypsin concentration. RESULTS: Patients with PD displayed decreased concentrations of fecal acetic, propionic, and butyric acid and increased concentrations of plasma acetic and propionic acid. Fecal acetic, isobutyric, and isovaleric acid were lower and plasma acetic and propionic acid were higher in patients with PD with constipation than in patients with PD without constipation. Constipation aggravated GBB permeability in patients with PD. Combined fecal and plasma SCFAs could discriminate patients with PD from healthy control subjects. Fecal SCFAs, except propionic acid, were negatively correlated with disease severity, while plasma acetic, propionic, and valeric acid showed a positive correlation. CONCLUSIONS: Our study showed alterations of fecal and plasma SCFAs in patients with PD that were associated with an impaired GBB and might be aggravated by constipation. © 2022 International Parkinson and Movement Disorder Society.

LncRNA HOXA-AS2 regulates microglial polarization via recruitment of PRC2 and epigenetic modification of PGC-1α expression.

BACKGROUND: Microglia-mediated neuroinflammation plays an important role in Parkinson's disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype. Hence, promoting microglia toward the anti-inflammatory M2 phenotype is a potential therapeutic approach for PD. Long noncoding RNAs (lncRNAs) are crucial in the progression of neurodegenerative diseases, but little is known about their role in microglial polarization in PD. METHODS: In our study, we profiled the expression of lncRNAs in the peripheral blood mononuclear cells (PBMCs) of PD patients using a microarray. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers both in vitro and in vivo. RIP and ChIP assays were analyzed for the underlying mechanism of lncRNA regulating microglial polarization. RESULTS: We found that HOXA-AS2 was upregulated in the PBMCs of PD patients and negatively associated with peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α) expression. Moreover, HOXA-AS2 knockdown significantly repressed microglial M1 polarization and promoted M2 polarization by regulating PGC-1α expression. Mechanistic investigations demonstrated that HOXA-AS2 could directly interact with polycomb repressive complex 2 (PRC2) and modulate the histone methylation of the promoter of PGC-1α. CONCLUSIONS: Our findings identify the upregulated lncRNA HOXA-AS2 promotes neuroinflammation by regulating microglial polarization through interacts with the PRC2 complex and epigenetically silencing PGC-1α. HOXA-AS2 may be a potential therapeutic target for microglia-mediated neuroinflammation in patients with PD.

Gut metagenomics-derived genes as potential biomarkers of Parkinson's disease.

Identification of the gut microbiome compositions associated with disease has become a research focus worldwide. Emerging evidence has revealed the presence of gut microbiota dysbiosis in Parkinson's disease. In this study, we aimed to identify the gut microbiome associated with Parkinson's disease and subsequently to screen and to validate potential diagnostic biomarkers of Parkinson's disease. This case-control study investigated gut microbial genes in faeces from 40 volunteer Chinese patients with Parkinson's disease and their healthy spouses using shotgun metagenomic sequencing. Furthermore, the identified specific gut microbial gene markers were validated with real-time PCR in an independent Chinese cohort of 78 Parkinson's disease patients, 75 control subjects, 40 patients with multiple system atrophy and 25 patients with Alzheimer's disease. We developed the first gut microbial gene catalogue associated with Parkinson's disease. Twenty-five gene markers were identified that distinguished Parkinson's disease patients from healthy control subjects, achieving an area under the receiver operating characteristic curve (AUC) of 0.896 (95% confidence interval: 83.1-96.1%). A highly accurate Parkinson's disease index, which was not influenced by disease severity or Parkinson's disease medications, was created. Testing these gene markers using quantitative PCR distinguished Parkinson's disease patients from healthy controls not only in the 40 couples (AUC = 0.922, 95% confidence interval: 86.4-98.0%), but also in an independent group of 78 patients with Parkinson's disease and 75 healthy control subjects (AUC = 0.905, 95% confidence interval: 86.0-95.1%). This classifier also performed a differential diagnosis power in discriminating these 78 patients with Parkinson's disease from a cohort of 40 patients with multiple system atrophy and 25 patients with Alzheimer's disease based on the panel of 25 biomarkers. Based on our results, the identified Parkinson's disease index based on the gene set from the gut microbiome may be a potential diagnostic biomarker of Parkinson's disease.

Evaluation of tremor interference with control of voluntary reaching movements in patients with Parkinson's disease.

BACKGROUND: A large population of patients with Parkinson's disease (PD) displays the symptom of resting tremor. However, the extent that resting tremor may affect the performance of movement control has not been evaluated specifically. This study aims at establishing methods to quantitatively evaluate motor performance in PD patients with tremor, and at analyzing the interfering effects of tremor on control of reaching movements. METHODS: Ten PD patients with tremor and Ten healthy control subjects were recruited to participate in this study. All patients and healthy control subjects performed point-to-point reaching movements with their tremor affected arm or preferred arm. We verified that a smoothing model of minimum-jerk trajectory (MJT) can be used to extract voluntary movement trajectory from tremor-corrupted movement trajectory in the reaching tasks by the patients. Performance indices of reaction time (RT) and movement time (MT) of reaching movements by the PD subjects with tremor were evaluated using MJT trajectories. Differences of RT and MT between the recorded trajectories and MJT in PD and control subjects were calculated to investigate the extent that tremor may affect their motor performance. Linear mixed-effects model was used to identify the contributions of tremor, bradykinesia and rigidity to the performance indices of RT and MT based on UPDRS scores. The power spectrum densities (PSD) of tremor were also evaluated using hand velocities to represent tremor intensity and to analyze their correlations with RT and MT. RESULTS: The MJT model demonstrated good fit to recorded trajectory with a more consistent estimation of motor performance for both PD and control subjects. The RT and MT of patients were found to be 43.4 and 79.5% longer respectively than those of healthy control subjects. Analysis of the linear mixed-effects model was not able to reveal that tremor, bradykinesia and rigidity each had a significant contribution to RT or MT in PD patients with tremor. However, the PSD of tremor was found to correlate significantly to RT, but not to MT, in both linear regression and linear mixed-effects model. CONCLUSIONS: The minimum-jerk trajectory and power spectrum densities are effective quantitative tools for evaluating motor performance for PD patients with tremor. Resting tremor is one of the factors prolonging the initiation of voluntary reaching movement in these patients.

Parkinson's disease-related DJ-1 modulates the expression of uncoupling protein 4 against oxidative stress.

Loss of function mutations of DJ-1 (PARK7) have been linked to the pathogenesis of Parkinson's disease. Antioxidative stress is one of the multi-protective functions of DJ-1, and oxidation of cysteine 106 has been proposed to regulate the protective activity of DJ-1. Uncoupling protein 4 (UCP4) is located in the inner membrane of mitochondria and functions to protect against oxidative stress. In this study, we used neuronal (SH-SY5Y) cells and DJ-1 knockout mice to elucidate whether DJ-1 regulated oxidative stress via modulating the expression of UCP4, and the underlying mechanism. The downstream products of oxidative stress, mitochondrial membrane potential (ΔΨm) and cell viability were also investigated. We found that UCP4 was up-regulated upon 1-methyl-4-phenylpyridinium (MPP+ ) stimulation in SH-SY5Y cells, which was enhanced by wild type DJ-1 and alleviated by DJ-1 knockdown. Expression of UCP4 in DJ-1 knockout mice was lower compared with wild-type mice. In addition, up-regulation of UCP4 was alleviated by inhibition of oxidized DJ-1, and enhanced by increase in oxidized DJ-1 under conditions of oxidative stress using western blot analysis. Moreover, over-expression of UCP4 in DJ-1 knockdown cells partially reversed the decrease in cell viability, ΔΨm, as well as the increase in products of oxidative stress upon MPP+ stimulation. Furthermore analysis showed that DJ-1 regulated transcriptional activity of UCP4 partially via Nuclear factor-kappa B (NF-κB) pathway in the presence of MPP+ . Together, our results suggested DJ-1 might regulate the expression of UCP4 by oxidation of DJ-1 and partially via NF-κB pathway in its protective response to oxidative stress.

Purinergic receptor P2Y6 contributes to 1-methyl-4-phenylpyridinium-induced oxidative stress and cell death in neuronal SH-SY5Y cells.

Oxidative stress and neural degeneration have been shown to be involved in the pathogenesis of Parkinson's disease (PD). The P2Y6 purinergic receptor (P2Y6R) has been shown to participate in the activation of microglia and the production of pro-inflammatory factors induced by lipopolysaccharide to cause neuronal loss. However, the function of P2Y6R during oxidative stress in neurons is unclear. In the present study, 1-methyl-4-phenylpyridinium (MPP+ ) treatment increased the level of UDP/P2Y6R on neuronal SH-SY5Y cells. Importantly, pharmacological inhibition of P2Y6R or knockdown of P2Y6R using a siRNA exerted an increased protective effect by preventing MPP+ -induced increases in the levels of reactive oxygen species (ROS), superoxide anion, inducible nitric oxide synthase (iNOS), and malondialdehyde (MDA) and down-regulation of superoxide dismutase 1 (SOD1) expression. UDP, an agonist of P2Y6R, enhanced the effects of MPP+ , which was also inhibited by apyrase or MRS2578. Additionally, P2Y6R knockdown also significantly reversed both the loss of cell viability and the increase in the levels of phosphorylated extracellular signal-regulated protein kinase (p-ERK1/2) and p38 (p-p38) caused by MPP+ stimulation. However, the inhibition of the ERK1/2 and p38 kinase signaling pathways had no effect on P2Y6R expression. Taken together, these results support the hypothesis that P2Y6R expressed on neuronal SH-SY5Y cell is associated with the progression of oxidative stress and cell death induced by MPP+ , suggesting that P2Y6R may play an important role in the pathogenesis of PD.

Alteration of the fecal microbiota in Chinese patients with Parkinson's disease.

Emerging evidences suggest that gut microbiota dysbiosis plays a role in Parkinson's disease (PD). However, the alterations in fecal microbiome in Chinese PD patients remains unknown. This case-control study was conducted to explore fecal microbiota compositions in Chinese PD patients. Microbiota communities in the feces of 45 patients and their healthy spouses were investigated using high-throughput Illumina Miseq sequencing targeting the V3-V4 region of 16S ribosomal RNA (rRNA) gene. The relationships between fecal microbiota and PD clinical characteristics were analyzed. The structure and richness of the fecal microbiota differed between PD patients and healthy controls. Genera Clostridium IV, Aquabacterium, Holdemania, Sphingomonas, Clostridium XVIII, Butyricicoccus and Anaerotruncus were enriched in the feces of PD patients after adjusting for age, gender, body mass index (BMI), and constipation. Furthermore, genera Escherichia/Shigella were negatively associated with disease duration. Genera Dorea and Phascolarctobacterium were negatively associated with levodopa equivalent doses (LED). Among the non-motor symptoms (NMSs), genera Butyricicoccus and Clostridium XlVb were associated with cognitive impairment. Overall, we confirmed that gut microbiota dysbiosis occurs in Chinese patients with PD. A well-controlled population involved was beneficial for the identification of microbiota associated with diseases. Additionally, the fecal microbiota was closely related to PD clinical characteristics. Elucidating these differences in the fecal microbiome will provide a foundation to improve our understanding the pathogenesis of PD and to support the potentially therapeutic options modifying the gut microbiota.

Resveratrol regulates microglia M1/M2 polarization via PGC-1α in conditions of neuroinflammatory injury.

Microglia are the primary cells that exert immune function in the central nervous system (CNS), and accumulating evidence suggests that microglia act as key players in the initiation of neurodegenerative diseases. It is now well recognized that microglia have functional plasticity and dual phenotypes, proinflammatory M1 and anti-inflammatory M2 phenotypes. Inhibiting the M1 phenotype while stimulating the M2 phenotype has been suggested as a potential therapeutic approach for the treatment of neuroinflammation-related diseases. Resveratrol has been demonstrated to exert anti-inflammatory effects by suppressing M1 microglia activation. However, the role of resveratrol in regulating microglia polarization and the molecular mechanisms involved have not been fully clarified. In this study, we tested whether resveratrol could suppress microglia activation by promoting microglia polarization toward the M2 phenotype via PGC-1α by measuring M1 and M2 markers in vitro and in vivo. Our study demonstrated that resveratrol reduced inflammatory damage and promoted microglia polarization to the M2 phenotype in LPS-induced neuroinflammation. In addition, resveratrol ameliorated LPS-induced sickness behavior in mice. The promoting effects of resveratrol on M2 polarization were attenuated by knocking down PGC-1α. PGC-1α not only suppressed LPS-evoked M1 marker expression by inhibition of NF-κB activity but also increased M2 marker expression by coactivation of the STAT6 and STAT3 pathways. We propose that overexpression PGC-1α by resveratrol could be a potential therapeutic approach to suppress neuroinflammation by regulating microglia polarization.

A visualized model for identifying optimal candidates for aggressive locoregional surgical treatment in patients with bone metastases from breast cancer.

Background: The impact of surgical resection of primary (PTR) on the survival of breast cancer (BC) patients with bone metastasis (BM) has been preliminarily investigated, but it remains unclear which patients are suitable for this procedure. Finally, this study aims to develop a predictive model to screen BC patients with BM who would benefit from local surgery. Methods: BC patients with BM were identified using the Surveillance, Epidemiology, and End Results (SEER) database (2010 and 2015), and 39 patients were obtained for external validation from an Asian medical center. According to the status of local surgery, patients were divided into Surgery and Non-surgery groups. Propensity score matching (PSM) analysis was performed to reduce selection bias. Kaplan-Meier (K-M) survival and Cox regression analyses were conducted before and after PSM to study the survival difference between the two groups. The survival outcome and treatment modality were also investigated in patients with different metastatic patterns. The logistic regression analyses were utilized to determine significant surgery-benefit-related predictors, develop a screening nomogram and its online version, and quantify the beneficial probability of local surgery for BC patients with BM. Receiver operating characteristic (ROC) curves, the area under the curves (AUC), and calibration curves were plotted to evaluate the predictive performance and calibration of this model, whereas decision curve analysis (DCA) was used to assess its clinical usefulness. Results: This study included 5,625 eligible patients, of whom 2,133 (37.92%) received surgical resection of primary lesions. K-M survival analysis and Cox regression analysis demonstrated that local surgery was independently associated with better survival. Surgery provided significant survival benefits in most subgroups and metastatic patterns. After PSM, patients who received surgery had a longer survival time (OS: 46 months vs. 32 months, p < 0.001; CSS: 50 months vs. 34 months, p < 0.001). Logistic regression analysis determined six significant surgery-benefit-related variables: T stage, radiotherapy, race, liver metastasis, brain metastasis, and breast subtype. These factors were combined to establish the nomogram and a web probability calculator (https://sunshine1.shinyapps.io/DynNomapp/), with an AUC of 0.673 in the training cohort and an AUC of 0.640 in the validation cohort. The calibration curves exhibited excellent agreement. DCA indicated that the nomogram was clinically useful. Based on this model, surgery patients were assigned into two subsets: estimated sur-non-benefit and estimated sur-benefit. Patients in the estimated sur-benefit subset were associated with longer survival (median OS: 64 months vs. 33 months, P < 0.001). Besides, there was no difference in survival between the estimated sur-non-benefit subset and the non-surgery group. Conclusion: Our study further confirmed the significance of local surgery in BC patients with BM and proposed a novel tool to identify optimal surgical candidates.

Sodium butyrate ameliorates gut dysfunction and motor deficits in a mouse model of Parkinson's disease by regulating gut microbiota.

Background: A growing body of evidence showed that gut microbiota dysbiosis might be associated with the pathogenesis of Parkinson's disease (PD). Microbiota-targeted interventions could play a protective role in PD by regulating the gut microbiota-gut-brain axis. Sodium butyrate (NaB) could improve gut microbiota dysbiosis in PD and other neuropsychiatric disorders. However, the potential mechanism associated with the complex interaction between NaB and gut microbiota-gut-brain communication in PD needs further investigation. Methods: C57BL/6 mice were subjected to a rotenone-induced PD model and were treated intragastrically with NaB for 4 weeks. The gut function and motor function were evaluated. The α-synuclein expression in colon and substantia nigra were detected by western blotting. Tyrosine hydroxylase (TH)-positive neurons in substantia nigra were measured by immunofluorescence. Moreover, gut microbiota composition was analyzed by 16S rRNA sequencing. Fecal short chain fatty acids (SCFAs) levels were determined by liquid chromatography tandem mass spectrometry (LC-MS). The levels of glucagon like peptide-1 (GLP-1) in tissues and serum were evaluated using enzyme-linked immunosorbent assay (ELISA). Results: NaB ameliorated gut dysfunction and motor deficits in rotenone-induced mice. Meanwhile, NaB protected against rotenone-induced α-synuclein expression in colon and substantia nigra, and prevented the loss of TH-positive neurons. In addition, NaB could remodel gut microbiota composition, and regulate gut SCFAs metabolism, and restore GLP-1 levels in colon, serum, and substantia nigra in PD mice. Conclusion: NaB could ameliorate gut dysfunction and motor deficits in rotenone-induced PD mice, and the mechanism might be associated with the regulation of gut microbiota dysbiosis.

Effect of airflow angle on abaxial surface deposition in air-assisted spraying.

Air-assisted sprayers are widely used in orchards for pest and disease control. However, air-assisted spray deposition on the abaxial surface of leaves is often limited. In this study, a method to achieve satisfactory spray deposition on the abaxial leaf surface and an assessment of factors that affect abaxial surface deposition were investigated. The effects of leaf angle, wind speed, platform velocity, and nozzle type were assessed. Abaxial surface coverage was significantly affected by leaf angle, wind speed, and nozzle type, of which the leaf angle had the strongest impact. The leaf angle largely determines the abaxial surface area exposed to the wind field. When the abaxial surface is situated leeward, deposition of droplets on the abaxial surface is difficult. Therefore, to improve abaxial surface exposure for field application, the exposure probability of the abaxial surface at different angles between the leaf and the airflow (α) was examined. The relationship was well represented by a logistic growth curve. The exposure probability exceeded 95% when the α value was greater than 5°. The latter finding was verified by conducting a field application in which the deposition efficiency on the abaxial surface (DEAS) was calculated. Adjustment of the airflow angle based on the theoretical value achieved DEAS of 49.9% and 109.3% in the middle and upper layers of the canopy, respectively, whereas the DEAS was less than 30% if the airflow angle was not adjusted. This is caused by the difference in the exposure probability of the back of the leaf. The results provide a reference for adjustment of the wind field of air-assisted sprayers in field applications.

Effect of Lacticaseibacillus paracasei strain Shirota supplementation on clinical responses and gut microbiome in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor issues and a range of non-motor symptoms. Microbial therapy may be a useful approach for the treatment of PD. However, comprehensive analyses of the impact of probiotic supplementation on motor and non-motor symptoms are still lacking and the mechanisms whereby the treatment works remain unclear. This study investigated Lacticaseibacillus paracasei strain Shirota (LcS) supplementation on clinical responses, gut microbiota and faecal metabolites in PD patients. Patients (n = 128) were randomised to receive either probiotics (LcS-fermented milk, containing 1 × 1010 living LcS cells) or placebo for 12 weeks. All participants were examined and the basic clinical features were recorded using questionnaires. Fecal and blood samples were collected at the baseline and after 12 weeks for further omics analysis. We found that LcS intervention significantly alleviated patients' constipation-related symptoms and non-motor symptoms. We found no significant shifts in the composition of gut microbiota or faecal metabolites. Several taxa were differentially abundant between the groups, especially with regard to LcS intake, which increased the abundance of the genus Lacticaseibacillus in the probiotic group compared with those at the baseline and in the placebo group. The faecal concentration of L-tyrosine was significantly decreased and the plasma concentration of L-tyrosine was increased in the probiotic group compared with the placebo group. Our study demonstrated that although supplementation with LcS did not induce major changes in the global gut microbiome, the probiotic had favorable effects in managing constipation and other non-motor symptoms in PD patients. This study was registered at the Chinese Clinical Trial Registry: ChiCTR1800016795.

Plasma branched-chain and aromatic amino acids correlate with the gut microbiota and severity of Parkinson's disease.

Disturbances of circulating amino acids have been demonstrated in patients with Parkinson's disease (PD). However, there have been no consistent results for branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs), and related factors have not been explored. We aimed to explore plasma BCAA and AAA profiles in PD patients, and identify their correlations with clinical characteristics and the gut microbiota. Plasma BCAA (leucine, isoleucine, and valine) and AAA (tyrosine and phenylalanine) levels were measured in 106 PD patients and 114 controls. Fecal samples were collected from PD patients for microbiota sequencing and functional analysis. We found that plasma BCAAs and tyrosine were decreased in PD patients. BCAAs and AAAs were correlated with clinical characteristics and microbial taxa, and, in particular, they were negatively correlated with the Hoehn and Yahr stage. Compared with early PD patients, BCAA and AAA levels were even lower, and microbial composition was altered in advanced PD patients. Predictive functional analysis indicated that predicted genes numbers involved in BCAA biosynthesis were lower in advanced PD patients. What's more, the fecal abundances of critical genes (ilvB, ilvC, ilvD, and ilvN) involved in BCAA biosynthesis were reduced and fecal BCAA concentrations were lower in advanced PD patients. In conclusion, the disturbances of plasma BCAAs and AAAs in PD patients may be related to the gut microbiota and exacerbated with PD severity. The microbial amino acid metabolism may serve as a potential mechanistic link.

Analysis of serum levels of organochlorine pesticides and related factors in Parkinson's disease.

BACKGROUND: There is evidence that environmental factors contribute to the onset and progression of Parkinson's disease (PD). Pesticides are a class of environmental toxins that are linked to increased risk of developing PD. However, few studies have investigated the association between specific pesticides and PD, especially in China, which was one of the first countries to adopt the use of pesticides. METHODS: In this study, serum levels of 19 pesticides were measured in 90 patients with PD and 90 healthy spouse controls. We also analyzed the interaction between specific pesticides and PD. In addition, the association between pesticides and clinical features of PD was also investigated. Finally, we investigated the underlying mechanism of the association between pesticides and PD. RESULTS: Serum levels of organochlorine pesticides, which included α-hexachlorocyclohexane (HCH), ß-HCH, γ-HCH, δ-HCH, propanil, heptachlor, dieldrin, hexachlorobenzene, p,p'-dichlorodiphenyltrichloroethane and o,p'-dichloro-diphenyl-trichloroethane were higher in PD patients than controls. Moreover, α-HCH and propanil levels were associated with PD. Serum levels of dieldrin were associated with Hamilton Depression Scale and Montreal Cognitive Assessment scores in PD patients. In SH-SY5Y cells, α-HCH and propanil increased level of reactive oxygen species and decreased mitochondrial membrane potential. Furthermore, propanil, but not α-HCH, induced the aggregation of α-synuclein. CONCLUSIONS: This study revealed that elevated serum levels of α-HCH and propanil were associated with PD. Serum levels of dieldrin were associated with depression and cognitive function in PD patients. Moreover, propanil, but not α-HCH, induced the aggregation of α-synuclein. Further research is needed to fully elucidate the effects of pesticides on PD.

Sodium butyrate attenuates rotenone-induced toxicity by activation of autophagy through epigenetically regulating PGC-1α expression in PC12 cells.

Short-chain fatty acids (SCFAs) are considered the key molecular link between gut microbiota and pathogenesis of Parkinson's disease (PD). However, the role of SCFAs in PD pathogenesis is controversial. Autophagy is important for the degradation of α-synuclein, which is critical to the development of PD. However, whether SCFAs can regulate autophagy in PD remains unknown. We aimed to investigate the role of SCFAs and explore the potential mechanisms in rat dopaminergic PC12 cells treated with rotenone. Expression levels of α-synuclein, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and microtubule-associated protein 1 light chain 3 beta (LC3B)-II were detected by Western blot. Histone acetylation levels at PGC-1α promoter region were measured using chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). Among the three SCFAs, sodium butyrate (NaB) protected against rotenone-induced toxicity. NaB activated autophagy pathway and reduced rotenone-induced α-synuclein expression through the activation of autophagy. Notably, NaB activated autophagy pathway through upregulating PGC-1α expression. More importantly, NaB promoted the levels of histone 3 lysine 9 acetylation (H3K9Ac) and histone 3 lysine 27 acetylation (H3K27Ac) at PGC-1α promoter region, indicating that NaB promotes PGC-1α expression via histone acetylation modification. In conclusion, NaB can protect against rotenone-induced toxicity through activation of the autophagy pathway by upregulating PGC-1α expression via epigenetic modification.

Associations between the use of ß-adrenoceptor acting drugs and the risk of dementia in older population.

Objective: Age-related decline within the noradrenergic system is associated with reduced cognition. The ß-adrenoceptors are widely expressed in the brain as well as in the peripheral. Medications targeting ß-adrenoceptor activity have been widely used in older adults. The aim of this study was to explore the associations between ß-adrenoceptor acting drugs and the risk of dementia in the older population. Methods: The subjects' information was collected from the electronic medical record (EMR) database. A propensity score matching strategy was conducted to select control participants for users of ß2-agonists or ß-antagonists. Logistic regression analysis was performed to estimate the risk of dementia with the use of ß2-agonists or ß-antagonists. Results: A total of 1,429 participants in the EMR database were included in the study. The use of ß2-agonists was strongly associated with a decreased risk of dementia [OR = 0.324, 95% confidence interval (CI): 0.149-0.707, P = 0.005]. This decreased risk showed a statistically significant inverse time-dependent pattern (P trend = 0.014). However, the use of non-selective ß-antagonists significantly correlated with an increased dementia risk (OR = 1.961, 95% CI: 1.144-3.359, P = 0.014), although no time-dependent manner was found (P trend = 0.220). There was no association between selective ß1-antagonists usage and dementia risk (OR = 1.114, P = 0.625). Conclusion: The use of ß-adrenoceptor acting drugs seems to be associated with the risk of dementia. Pharmacological interventions modulating ß2-adrenoceptor activity might be a potential target in therapeutics for dementia.

Association Between Microbial Tyrosine Decarboxylase Gene and Levodopa Responsiveness in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Interindividual variability in levodopa efficacy is a challenge for the personalized treatment of Parkinson disease (PD). Gut microbiota might represent a new approach for personalized medicine. Recently, a novel microbial levodopa metabolism pathway was identified, which is mediated by tyrosine decarboxylase mainly encoded by tyrosine decarboxylase gene (tyrDC) in Enterococcus faecalis. In this study, we aimed to identify whether the abundance of microbial tyrDC gene and E faecalis is associated with levodopa responsiveness and could predict the drug response. METHODS: This cross-sectional study enrolled patients with PD between December 2019 and January 2022 and evaluated levodopa responsiveness using a levodopa challenge test. Patients were stratified into moderate and good responders based on levodopa responsiveness. The tyrDC gene and E. faecalis abundance in fecal samples were measured using quantitative real-time PCR. Plasma levodopa concentrations were measured using liquid chromatography-tandem mass spectrometry analysis. The predictive models for levodopa responsiveness were constructed and verified through cross-validation and external validation. RESULTS: A total of 101 patients with PD were enrolled in the primary cohort and 43 were enrolled in the external validation cohort. Moderate responders had higher abundances of the tyrDC gene (3.6 [3.1-4.3] vs 2.6 [2.1-2.9], p < 0.001) and E faecalis (3.2 [2.5-4.4] vs 2.6 [2.1-3.6], p = 0.010) than good responders. The tyrDC gene abundance was independently associated with levodopa responsiveness (OR: 5.848; 95% CI: 2.664-12.838; p < 0.001). Notably, tyrDC gene abundance showed certain discriminative power for levodopa responsiveness in primary cohort (sensitivity: 80.0%; specificity: 84.3%; area under the curve [AUC]: 0.85; 95% CI: 0.77-0.93; p < 0.001) and external validation cohort (sensitivity: 85.0%; specificity: 95.7%; AUC: 0.95; 95% CI: 0.89-1.02; p < 0.001). The prediction of levodopa responsiveness based on tyrDC gene abundance had good calibration and discrimination in cross-validation (C-index in training and test sets: 0.856 and 0.851, respectively) and external validation (C-index: 0.952). DISCUSSION: The microbial tyrDC gene abundance could serve as a potential biomarker of levodopa responsiveness. Novel strategies targeting the tyrDC gene may provide new approaches for personalized levodopa treatment.

Plasma Short-Chain Fatty Acids Differences in Multiple System Atrophy from Parkinson's Disease.

BACKGROUND: Multiple system atrophy (MSA) and Parkinson's disease (PD) have overlapping symptoms, making diagnosis challenging. Short-chain fatty acids (SCFAs) are produced exclusively by gut microbiota and were reduced in feces of MSA patients. However, plasma SCFA concentrations in MSA patients have not been investigated. OBJECTIVE: We aimed to investigate the plasma SCFAs in MSA patients and to identify the potential differential diagnostic ability. METHODS: Plasma SCFA were measured in 25 MSA patients, 46 healthy controls, and 46 PD patients using gas chromatography-mass spectrometry. Demographic and clinical characteristics of the participants were evaluated. RESULTS: Acetic acid concentration was lower in MSA patients than in healthy controls. Acetic acid and propionic acid concentrations were lower in MSA and MSA with predominant parkinsonism (MSA-P) patients than in PD patients. A receiver operating characteristic curve (ROC) analysis revealed reduced acetic acid concentration discriminated MSA patients from healthy controls with 76% specificity but only 57% sensitivity and an area under the curve (AUC) of 0.68 (95% confidence interval (CI): 0.55-0.81). Combined acetic acid and propionic acid concentrations discriminated MSA patients from PD patients with an AUC of 0.82 (95% CI: 0.71-0.93), 84% specificity and 76% sensitivity. Especially, with combined acetic acid and propionic acid concentrations, MSA-P patients were separated from PD patients with an AUC of 0.89 (95% CI: 0.80-0.97), 91% specificity and 80% sensitivity. CONCLUSION: Plasma SCFAs were decreased in MSA patients. The combined acetic acid and propionic acid concentrations may be a potential biomarker for differentiating MSA patients from PD patients.

Findings in Chinese Patients With Parkinson's Disease: A Content Analysis From the SML Study.

Social media listening (SML) is a new process for obtaining information from social media platforms to generate insights into users' experiences and has been used to analyze discussions about a multitude of diseases. To understand Parkinson's disease patients' unmet needs and optimize communication between doctors and patients, social media listening was performed to investigate concerns in Chinese patients. A comprehensive search of publicly available social media platforms with Chinese-language content posted between January 2005 and April 2019 in mainland China was performed using defined Parkinson's disease-related terms. After multiple steps of machine screening were performed, a series of posts were derived. The content was summarized and classified manually to analyze and map psychological insights, and descriptive statistics were applied to aggregate findings. A total of 101,899 patient-related posts formed the basis of this study. The topics mainly focused on motor symptoms (n = 54,983), choice of pharmaceutical drugs (n = 45,203) and non-motor symptoms (n = 44,855). The most common symptoms mentioned were tremor (54.5%), pain (22.9%), and rigidity (22.1%). Psychological burden (51%) and work/social burden (48%) were the most concerning burdens for patients and their families. The compound levodopa (43%) and dopamine agonists (23%) were the most common options for the patients, while concerns about new-generation anti-Parkinson's disease medication increased. The portraits of patients suggested varying characteristics across different periods and advocate for personalized service from doctors. In the management of patients, it is imperative to plan individualized therapy and education strategies as well as strategies for social support.

Hypermethylation of the Gene Coding for PGC-1α in Peripheral Blood Leukocytes of Patients With Parkinson's Disease.

Decreased expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is implicated in the pathophysiology of Parkinson's disease (PD). However, our understanding of the mechanism regulating the PGC-1α expression is still limited. We sought to determine whether the epigenetic modification of PPARGC1A (the gene encoding PGC-1α) could account for its diminished expression. We performed a study of PPARGC1A risk-SNP genotypes, methylation level, and the expression in blood from 171 subjects. The mean DNA methylation level of PPARGC1A intron 1 in patients with PD was higher than that in the controls (7.18 ± 1.74 vs. 6.36 ± 1.28, P = 0.007). A detailed comparison of the DNA methylation level at each CpG site showed that CpG_1, CpG_13.14, CpG_17.18, and CpG_20 were significantly hypermethylated in patients with PD. There was a significant negative correlation between PPARGC1A methylation and expression level (R = -0.404, P < 0.001). We found no correlations between the PPARGC1A methylation level and the clinical features, while the CpG_13.14 site methylation level was positively correlated with H&Y stage (R = 0.246, P = 0.020) and was increased in people carrying the rs2970848 AA genotype compared with that in carriers of the AG/GG genotype (7.27 ± 1.86 vs. 6.65 ± 1.92, P = 0.032). Our results support a link between PPARGC1A methylation, gene expression, and variability, which indicated that a novel epigenetic regulatory mechanism controlling PPARGC1A expression influences PD pathogenesis.