Identification of microRNAs for the early diagnosis of Parkinson's disease and multiple system atrophy.

MicroRNAs are reportedly involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease and multiple system atrophy. We previously identified 7 differentially expressed microRNAs in Parkinson's disease patients and control sera (miR-30c, miR-31, miR-141, miR-146b-5p, miR-181c, miR-214, and miR-193a-3p). To investigate the expression levels of the 7 serum microRNAs in Parkinson's disease and multiple system atrophy, 23 early Parkinson's disease patients (who did not take any anti- Parkinson's disease drugs), 23 multiple system atrophy patients, and 24 normal controls were recruited at outpatient visits in this study. The expression levels of the 7 microRNAs in serum were detected using quantitative real-time polymerase chain reaction. A receiver operating characteristic curve was used to evaluate whether microRNAs can differentially diagnose Parkinson's disease and multiple system atrophy. Clinical scales were used to analyze the correlations between serum microRNAs and clinical features. The results indicated that miR-214 could distinguish Parkinson's disease from the controls, and another 3 microRNAs could differentiate multiple system atrophy from the controls (miR-141, miR-193a-3p, and miR-30c). The expression of miR-31, miR-141, miR-181c, miR-193a-3p, and miR-214 were lower in multiple system atrophy than in Parkinson's disease (all P < 0.05). Combinations of microRNAs accurately discriminated Parkinson's disease from multiple system atrophy (area under the receiver operating characteristic curve = 0.951). For the correlation analysis, negative correlations were discovered between the expression of miR-214 and the Hamilton Anxiety Scale and Parkinson's Disease Non-Motor Symptom scores (all P < 0.05). Our results demonstrate that the distinctive characteristics of microRNAs differentiate Parkinson's disease and multiple system atrophy patients from healthy controls and may be used for the early diagnosis of Parkinson's disease and multiple system atrophy.

Metal-Organic Frameworks with Target-Specific Active Sites Switched by Photoresponsive Motifs: Efficient Adsorbents for Tailorable CO2 Capture.

Photoresponsive metal-organic frameworks (PMOFs) are of interest for tailorable CO2 adsorption. However, modulation of CO2 adsorption on PMOFs is based on steric hindrance or structural change owing to weak interactions between CO2 and active sites. It is challenging to fabricate PMOFs with strong but tailorable sites for CO2 adsorption. Now, the construction of PMOFs with target-specific (strong) active sites is achieved by introducing tetraethylenepentamine into azobenzene-functionalized MOFs for tailorable CO2 adsorption. Amines are specific active sites for CO2 , contributing to capture CO2 selectively. Cis/trans isomerization of azobenzene motifs trigged by UV/Vis light adjusts the electrostatic potential of amines significantly, leading to exposure/shelter of amines and modulation of CO2 adsorption on strong active sites. This system enables us to design adsorption processes for CO2 capture from mixtures, which is impossible to realize by traditional PMOFs.

Clinical outcomes of low-dose leflunomide for rheumatoid arthritis complicated with Hepatitis B virus carriage and safety observation.

OBJECTIVE: To study the clinical outcomes of low-dose leflunomide for rheumatoid arthritis (RA) complicated with hepatitis B virus (HBV) carriage and to observe the safety. METHODS: A total of 115 RA patients were divided into three groups according to the state of HBV. They were all given leflunomide to observe the clinical outcomes and whether HBV was activated. RESULTS: The indices (e.g. activity score) of all patients were significantly better after treatment than those before (P < 0.05), with 89.00% (92/115) of them reaching ACR20. Fourteen cases (12.2%) suffered from abnormal liver functions, and 5 cases who had HBV reactivation originated from the HBV carriage group. Neither the previous HBV infection group nor the infection-free group succumbed to HBV reactivation. The multiple regression model showed that the HBV reactivation risk of RA patients treated by leflunomide was increased by 30% by the basic state of hepatitis B as well as alanine transaminase level and swollen joint count before treatment. CONCLUSION: Leflunomide exerted satisfactory therapeutic effects on RA, but liver diseases, liver function, HBV-DNA load and the reactivation risks of carried HBV should be thoroughly checked and cautiously pondered.

Enhanced anti-inflammatory activity of chlorogenic acid via folic acid-TPGS-modified liposomes encapsulation: characterization and In vivo evaluation on colitis mice.

Introduction: Chlorogenic acid (CGA) has been identified to possess salient anti-inflammatory, antioxidant, and anticancer attributes. However, its application is limited by its instability and low bioavailability. Liposomes have been considered effective pharmaceutical delivery vehicles due to their ability to continuously release loaded drugs, improve drug stability, and display good biocompatibility. They can be easily modified by other small molecules to acquire additional biological functions. In this study, we developed and characterized folic acid-TPGS-modified chlorogenic acid liposome (FTCLP) and evaluated its anti-inflammatory activity. Methods: The successful encapsulation of CGA within FTCLP was confirmed through examination using electron microscopy, fourier-transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The in vitro release characteristics of FTCLP were evaluated using the dialysis bag membrane method. Meanwhile, a dextran sulfate sodium (DSS) -induced colitis model was employed to investigate the anti-inflammatory effect of FTCLP and its mechanism. Results: The FTCLP exhibited an encapsulation efficiency (EE) of 84.85 ± 1.20% and a drug loading (DL) of 11.67 ± 0.04%. The particle size of FTCLP was determined to be 150.63 ± 0.71 nm, with a polydispersity index (PDI) of 0.198 ± 0.02 and a zeta potential of 2.61 ± 0.38 mV. The in vitro release profile followed the Higuchi model, indicating sustained-release characteristics. The in vivo study demonstrated that FTCLP treatment was effective in improving the symptoms of DSS-induced inflammatory response, as evidenced by mitigation of weight loss, reduction in the disease activity index (DAI) score, restoration of colon length, and attenuation of colon tissue damage. Furthermore, the levels of pro-inflammatory cytokines, including interferon-gamma (INF-γ), interleukin-1 beta (IL-1ß), and interleukin-6 (IL-6), were markedly diminished in both the serum and colon tissue. FTCLP was also observed to suppress the expression of INF-γ, IL-1ß, IL-6, tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κB) p65, while concomitantly upregulating the expression of Janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3). Besides, the administration of FTCLP was found to result in an increase in the abundance of Lactobacillaceae and Peptostreptococcaceae, while decreasing the abundance of Bacteroidaceae, Rikenellaceae, and Helicobacteraceae. Conclusion: Following encapsulation of CGA within liposomes, FTCLP revealed favorable stability and sustained release properties, and enhanced the anti-inflammatory effects by modulating multiple inflammation-related biomarkers. FTCLP has the potential to be a safe and effective drug for targeted therapy of colitis.

Nonlinearity association between hyperuricemia and all-cause mortality in patients with chronic kidney disease.

Controversy surrounds the role of serum uric acid and whether treatment intervention is favorable in retarding the progression of chronic kidney disease (CKD). The association of serum uric acid levels and CKD patient mortality risk needs to be further determined by large sample cohort studies. The National Health and Nutrition Examination Survey participants with CKD from 1998 to 2017 were enrolled in the study. Multivariable Cox regression models were used to reveal the association of serum uric acid concentrations and CKD mortality risks. A total of 9891 CKD patients were enrolled in the study, and 3698 individuals died during the follow-up. Increasing serum uric acid levels are independently relevant to higher mortality risks of CKD patients (HR per SD increase). A restricted cubic spline curve showed a nonlinear association between serum uric acid and CKD mortality risks (p for nonlinearity = 0.046). CKD patients with higher levels of serum uric acid (≥ 5.900 mg/dL) show a significant increase in mortality risks (HR = 1.102, 95% CI 1.043-1.165). Sensitivity analysis demonstrated that the results were stable and robust. High serum uric acid levels (≥ 5.900 mg/dL) may be associated with increased mortality risks in CKD patients.

The association between plasma GPNMB and Parkinson's disease and multiple system atrophy.

AIMS: Parkinson's disease (PD), as the second most common neurodegenerative disorder, often presents diagnostic challenges in differentiation from other forms of Parkinsonism. Recent studies have reported an association between plasma glycoprotein nonmetastatic melanoma protein B (pGPNMB) and PD. METHODS: A retrospective study was conducted, comprising 401 PD patients, 111 multiple system atrophy (MSA) patients, 13 progressive supranuclear palsy (PSP) patients and 461 healthy controls from the Chinese Han population, with an assessment of pGPNMB levels. RESULTS: The study revealed that pGPNMB concentrations were significantly lower in PD and MSA patients compared to controls (area under the receiver operating characteristics curve (AUC) 0.62 and 0.74, respectively, P < 0.0001 for both), but no difference was found in PSP patients compared to controls (P > 0.05). Interestingly, the level of pGPNMB was significantly higher in PD patients than in MSA patients (AUC = 0.63, P < 0.0001). Furthermore, the study explored the association between pGPNMB levels and disease severity in PD and MSA patients, revealing a positive correlation in PD patients but not in MSA patients with both disease severity and cognitive impairment. CONCLUSION: This study successfully replicated prior findings, demonstrating an association between pGPNMB levels and disease severity, and also identified a correlation with cognitive impairment in PD patients of the Chinese Han population. Additionally, this study is the first to identify a significant difference in pGPNMB levels between MSA, PD, and normal controls. The data provide new evidence supporting the potential role of pGPNMB in the diagnosis and differential diagnosis of Parkinsonism.

Association Between Sleep Characteristics and Likelihood of Prodromal Parkinson's Disease: A Cross-Sectional Analysis in the HABIT Study.

Background: Sleep is critical in health problems including Parkinson's disease (PD). This study examined the association between sleep characteristics and the likelihood of prodromal PD. Methods: At baseline examination of the Heart and Brain Investigation in Taicang (HABIT) study, potential PD biomarkers were obtained for 8777 participants aged over 50 years, and the probability of prodromal PD was assessed based on the Chinese expert consensus and Movement Disorder Society (MDS) criteria. General and component sleep characteristics were evaluated by the Pittsburgh Sleep Quality Index (PSQI). Median regression was applied to examine the association between sleep and the probability of prodromal PD, adjusting for age, sex, education level, physical activity, obesity, fast plasma glucose, lipids, and hypertension. Results: Based on China criteria, a higher level of PSQI score was significantly associated with a higher probability of prodromal PD (ß = 0.02, 95% CI: 0.01-0.03) and a higher risk of having an increased probability of prodromal PD (OR = 1.04, 95% CI: 1.02-1.05). Compared to participants with good quality sleep, those with poor quality sleep had a 0.07% increased probability of prodromal PD (95% CI: 0.01-0.13) and a 19% increased risk of having a high prodromal PD probability (95% CI: 1.04-1.20). Similar associations between sleep quality and the probability of prodromal PD were also observed using the MDS criteria. Subjective sleep quality, sleep latency, habitual sleep efficiency, daytime dysfunction, and use of sleep medications were also associated with the probability of prodromal PD. Conclusion: Poor sleep quality was associated with a high probability of prodromal PD. Sleep may be helpful for understanding and intervention of prodromal PD.

Slow-wave sleep and REM sleep without atonia predict motor progression in Parkinson's disease.

BACKGROUND: Growing evidence supports the potential role of sleep in the motor progression of Parkinson's disease (PD). Slow-wave sleep (SWS) and rapid eye movement (REM) sleep without atonia (RWA) are important sleep parameters. The association between SWS and RWA with PD motor progression and their predictive value have not yet been elucidated. METHODS: We retro-prospectively analyzed clinical and polysomnographic data of 136 patients with PD. The motor symptoms were assessed using Unified Parkinson's Disease Rating Scale Part III (UPDRS III) at baseline and follow-up to determine its progression. Partial correlation analysis was used to explore the cross-sectional associations between slow-wave energy (SWE), RWA and clinical symptoms. Longitudinal analyses were performed using Cox regression and linear mixed-effects models. RESULTS: Among 136 PD participants, cross-sectional partial correlation analysis showed SWE decreased with the prolongation of the disease course (P = 0.046), RWA density was positively correlated with Hoehn & Yahr (H-Y) stage (tonic RWA, P < 0.001; phasic RWA, P = 0.002). Cox regression analysis confirmed that low SWE (HR = 1.739, 95% CI = 1.038-2.914; P = 0.036; FDR-P = 0.036) and high tonic RWA (HR = 0.575, 95% CI = 0.343-0.963; P = 0.032; FDR-P = 0.036) were predictors of motor symptom progression. Furthermore, we found that lower SWE predicted faster rate of axial motor progression (P < 0.001; FDR-P < 0.001) while higher tonic RWA density was associated with faster rate of rigidity progression (P = 0.006; FDR-P = 0.024) using linear mixed-effects models. CONCLUSIONS: These findings suggest that SWS and RWA might represent markers of different motor subtypes progression in PD.

Quantitative Transcranial Sonography Evaluation of Substantia Nigra Hyperechogenicity Is Useful for Predicting Levodopa-Induced Dyskinesia in Parkinson Disease.

Levodopa-induced dyskinesia (LID) is a common motor complication in Parkinson disease (PD). Abnormal substantia nigra hyperechogenicity (SN+), detected by transcranial sonography (TCS), plays an important role in the differential diagnosis of PD. The purpose of this study was to investigate the predictive performance of quantitative SN+ evaluations for LID. Five hundred sixty-two individuals were included in our analysis, and 198 individuals were followed up. These individuals were divided into two groups at baseline: the PD with LID (PD+LID) group and the PD without LID (PD-LID) group. The association between total hyperechogenic area of the SN on both sides (SNT) and LID was analyzed by binary logistic analysis. A binary logistic regression model including SNT was applied to establish a model for discriminating LID. At baseline, 105 (18.7%) individuals were diagnosed with LID. The PD+LID group had a longer disease duration, shorter education duration, higher levodopa equivalent doses, greater disease severity and larger SNT. A model combining clinical features and SNT was further established with better efficiency (area under the receiver operating characteristic curve = 0.839). One hundred ninety-eight individuals were followed up; individuals with a larger SNT and a higher predicted probability were more likely to develop LID in our follow-up. Our study determined that quantitative TCS evaluation of SN echogenicity is useful in predicting LID in PD.

Associations between variants in levodopa metabolic pathway genes and levodopa-induced dyskinesia in Parkinson's disease.

INTRODUCTION: Levodopa-induced dyskinesia (LID) is a common motor complication in Parkinson's disease (PD). Several genes in the levodopa metabolic pathway, such as COMT, DRDx and MAO-B, were reported associated with LID. However, there has been no systematic analyses between common variants in levodopa metabolic pathway genes and LID in a large sample of the Chinese population. METHODS: Through the whole exome sequencing (WES) and target region sequencing, we aimed to explore the potential associations between common single nucleotide polymorphisms (SNPs) in the levodopa metabolic pathway and LID in Chinese PD individuals. Five hundred and two PD individuals were enrolled in our study, among them, 348 individuals underwent WES, and 154 individuals underwent target region sequencing. We acquired the genetic profile of 11 genes including COMT, DDC, DRD1-5, SLC6A3, TH and MAO-A/B. We established a stepwise strategy to filter SNPs, which finally included 34 SNPs in our analyses. And we used a two-stage study, with discovery (348 individuals with WES) and the replication (all 502 individuals) to confirm our findings. RESULTS: Among the 502 PD individuals, 104 (20.7%) were diagnosed with LID. In the discovery stage, we found that COMT rs6269, DRD2 rs6275 and DRD2 rs1076560 were associated with LID. In the replication stage, associations between the three above-mentioned SNPs and LID were still present in all 502 individuals. CONCLUSION: We demonstrated that in the Chinese population, COMT rs6269, DRD2 rs6275 and rs1076560 were significantly associated with LID. And rs6275 was reported associated with LID for the first time.

Identifying the hub gene and immune infiltration of Parkinson's disease using bioinformatical methods.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder that affects 1%-2% of the population over 60 years old. Immune response dysfunction in the brain contributes to the occurrence and development of PD. This study aimed to uncover the potential diagnostic genes for PD and characterize the immune cell infiltrates. METHODS: We downloaded the microarray data of patients with PD samples from the Gene Expression Omnibus (GEO) database. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify the modules linked to PD in the GSE20163 dataset. Meanwhile, differentially expressed genes (DEGs) between the healthy control samples and PD samples were also identified. Then the PD-related genes were integrated based on the genes in the key module and DEGs. Functional enrichment analysis was used to explore the molecular mechanisms of these PD-related genes. Protein-protein interaction (PPI) network and least absolute shrinkage and selection operator (LASSO) analysis were used to further screen candidate genes for PD. Gene set enrichment analysis (GSEA) was applied to explore the biological functions of these candidate genes. The infiltration of immune cells was detected by single-sample gene set enrichment analysis (ssGSEA) algorithm in the GSE20163 dataset, and Pearson analysis was used to investigate the correlation of candidate genes with immune cells and immune checkpoint proteins. The expression of candidate genes in clinical samples was verified by qPCR. RESULTS: Altogether, we found a unique gene module related to PD, where 109 DEGs were identified in the GSE20163 dataset. Following these results, we screened 68 genes associated with PD. Gene Expression Omnibus (GEO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that these genes were markedly enriched in the pathway of synthesis and transport of neurons. Three candidate genes (SLC18A2, CALB1, and SYNGR3) were further identified in PD patients through PPI network and LASSO analysis. The receiver operating characteristic (ROC) curve indicated that the three candidate genes had a good performance in distinguishing the PD samples from healthy control samples. The proportions of the aDC, DC, NK CD56dim cells, and follicular helper T cells (TFH) were obviously different between the healthy control and PD samples. Moreover, CTLA4, LAG3, CEACAM1, and CD27 were highly expressed in the PD group. GSEA analysis for candidate genes revealed that they were all closely related to the neurogenic disease. Additionally, the three candidate genes were all strongly correlated with the above immune cells and immune checkpoint proteins. The qPCR results validated the expression differences of SLC18A2 and SYNGR3 in the clinical PD and control samples. CONCLUSION: The three candidate genes may be a useful tool for diagnosing PD patients. These findings provide a reference for exploring new therapeutic targets and strategies for PD treatment.

REM sleep without atonia and vestibular-evoked myogenic potentials: clinical brainstem dysfunction in early-stage Parkinson's disease and isolated REM sleep behavior disorder.

OBJECTIVE: To determine whether the onset of rapid eye movement (REM) sleep behavior disorder (RBD) is associated with changes in brainstem neuronal pathway dysfunction as reflected by vestibular-evoked myogenic potentials (VEMPs) and to evaluate associations between VEMPs and REM sleep without atonia (RSWA) in patients with early-stage Parkinson's disease (PD) and isolated RBD (iRBD). METHODS: Eighty-two early-stage PD patients, 40 iRBD patients, and 41 healthy control individuals underwent one-night video-polysomnography (vPSG) and VEMPs examination. We compared cervical (cVEMP), ocular (oVEMP), and masseter (mVEMP) VEMP parameters among PD with RBD (PD + RBD), PD without RBD (PD-RBD), iRBD, and control groups and analyzed correlations between VEMPs and RSWA in PD and iRBD groups. RESULTS: The PD + RBD group showed delays in bilateral cVEMP (Lp13, Ln23, Rn23: all p < 0.05) and oVEMP (Ln10, Rn10, Rp15: all p < 0.05) peak latencies compared with the PD-RBD group. Total cVEMP scores were higher in the PD + RBD group than in the iRBD group (p = 0.033). In PD patients, phasic RSWA was correlated with total cVEMP scores (p = 0.003), and tonic RSWA was correlated with left oVEMP scores (p = 0.013). CONCLUSIONS: Brainstem neurophysiology as evidenced by altered VEMPs in patients with PD and iRBD could reflect disease evolvement. Moreover, VEMPs alterations may vary depending on the presence of RBD in PD patients. The associations between altered RSWA and VEMP parameters highlight the meaningfulness of detecting brainstem dysfunction in early-stage PD.

Potential molecular mechanisms of Ermiao san in the treatment of hyperuricemia and gout based on network pharmacology with molecular docking.

A network pharmacology integrated molecular docking strategy was used to predict the underlying molecular mechanism of Ermiao san in the treatment of hyperuricemia and gout. Traditional Chinese medicine systems pharmacology (TCMSP) database and analysis platform were used to screen out the active compounds and their targets of Ermiao san. The disease target genes related to hyperuricemia (HUA) and gout were obtained by searching CTD, DisGeNET, DrugBank, GeneCards, OMIM, TTD, and PharmGKB databases with "Hyperuricemia" and "Gout" as keywords, respectively. The potential targets of Ermiao san in the treatment of HUA and gout were screened through a Venn diagram. The protein-protein interaction network was constructed using Cytoscape software. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were then conducted. Finally, some compounds and core targets were selected for molecular docking verification by Autodock Vina and Pymol software. Forty-six active compounds, such as quercetin, wogonin and beta-sitosterol, etc were identified. Ermiao san plays a therapeutic role in HUA and gout regulating various biological processes, cellular compounds, and molecular functions. The core targets of Ermiao san for treating HUA and gout are AT1 (namely Protein Kinase Bα), interleukin-1 beta, prostaglandin-endoperoxide synthase 2, JUN, etc. And the key pathways are nuclear factor-κB, interleukin-17 and tumor necrosis factor. The results of molecular docking analyses suggested that active compounds of Ermiao san could bind well to the core protein receptors. Ermiao san has a synergistic mechanism of multiple compounds, multiple targets, and multiple pathways in the treatment of HUA and gout, which provides a good theoretical basis for the clinical application.

Cognitive Performance is Associated with Altered Cerebral Hemodynamics Assessed by Transcranial Ultrasound in Parkinson's Disease.

Purpose: Cognitive impairment (CI) is a common but debilitating non-motor symptom in Parkinson's disease (PD). Although cerebrovascular functions are related to cognitive performance in healthy individuals, such a relation in PD remains elusive. This study aims to assess the association between cerebrovascular function and cognitive performance in PD individuals. Patients and Methods: Two-hundred-and-one PD individuals were retrospectively included. They were subsequently divided into two groups: PD with normal cognition (PD-NC) and PD with CI (PD-CI). Cerebral hemodynamic characteristics of the middle cerebral arteries were assessed by transcranial ultrasound. The association between scores in each cognitive domain and cerebral hemodynamic parameters was further analyzed using regression analyses. Additionally, a binary logistic regression model with backward stepwise procedure was applied to build the model for discriminating CI in PD individuals. An independent dataset of additional 46 PD individuals was used further. Results: The PD-CI group showed a relatively lower end-diastolic blood flow velocity (EDV, p < 0.05) and a higher resistive index (RI, p < 0.05) compared to the PD-NC group. RI showed significant associations with the memory item score of Montreal Cognitive Assessment (p < 0.05). A model combining clinical and hemodynamic variables was established with optimal efficiency (area under the curve, AUC = 0.651). Further replication of the model in an independent dataset yielded a great consistency (AUC = 0.704). Conclusion: In our study, cerebrovascular functions were significantly associated with the cognitive performance in PD individuals, especially with the memory task. The established model was effective in identifying CI in PD individuals, which might be a potentially useful tool to screen the cognitive decline in PD individuals at an early stage of the disease. Further studies with larger sample sizes in different populations are warranted.