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Levodopa is the mainstay of treatments for Parkinson's disease (PD), but large heterogeneity exists in patient response. Increasing evidence implicates bile acids (BAs) involved in the pathogenesis of PD. Furthermore, BAs have also participated in drug bioavailability. However, the impact of BAs on levodopa response (LR) has not been investigated. This study evaluated the association between fecal BAs and LR. Levodopa challenge test (LCT) was conducted in 92 PD patients to assess LR. A total of 36 fecal BAs and plasma levodopa concentrations were detected using LC-MS/MS. The difference of BAs between subgroups with bottom and top 30% LR were analyzed and fecal samples from the two groups were collected for metagenomic shotgun analysis. No fecal BAs were significantly correlated with LR, except for chenodeoxycholic acid-3-ß-D-glucuronide (CDCA-3-ß-glucuronide, R = -0.228, p-value = 0.039). We found no significant difference in BAs between subgroups with bottom and top 30% LR. What is more, no significant changes in bacterial species composition related to bile acids metabolism or in the proportional representation of genes encoding known bile acids enzymes were observed between the groups. Overall, our data do not support an association between fecal BAs and levodopa response in PD patients. More precise macro-metabolomic approaches are needed to reveal the potential association between gut microbial interactions and the treatment effect of levodopa.
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Objective: Chronic subdural hematoma (CSDH) is a neurological condition with high recurrence rates, primarily observed in the elderly population. Although several risk factors have been identified, predicting CSDH recurrence remains a challenge. Given the potential of machine learning (ML) to extract meaningful insights from complex data sets, our study aims to develop and validate ML models capable of accurately predicting postoperative CSDH recurrence. Methods: Data from 447 CSDH patients treated with consecutive burr-hole irrigations at Wenzhou Medical University's First Affiliated Hospital (December 2014-April 2019) were studied. 312 patients formed the development cohort, while 135 comprised the test cohort. The Least Absolute Shrinkage and Selection Operator (LASSO) method was employed to select crucial features associated with recurrence. Eight machine learning algorithms were used to construct prediction models for hematoma recurrence, using demographic, laboratory, and radiological features. The Border-line Synthetic Minority Over-sampling Technique (SMOTE) was applied to address data imbalance, and Shapley Additive Explanation (SHAP) analysis was utilized to improve model visualization and interpretability. Model performance was assessed using metrics such as AUROC, sensitivity, specificity, F1 score, calibration plots, and decision curve analysis (DCA). Results: Our optimized ML models exhibited prediction accuracies ranging from 61.0% to 86.2% for hematoma recurrence in the validation set. Notably, the Random Forest (RF) model surpassed other algorithms, achieving an accuracy of 86.2%. SHAP analysis confirmed these results, highlighting key clinical predictors for CSDH recurrence risk, including age, alanine aminotransferase level, fibrinogen level, thrombin time, and maximum hematoma diameter. The RF model yielded an accuracy of 92.6% with an AUC value of 0.834 in the test dataset. Conclusion: Our findings underscore the efficacy of machine learning algorithms, notably the integration of the RF model with SMOTE, in forecasting the recurrence of postoperative chronic subdural hematoma. Leveraging the RF model, we devised an online calculator that may serve as a pivotal instrument in tailoring therapeutic strategies and implementing timely preventive interventions for high-risk patients.
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Osteoporosis is a progressive skeletal disease which is characterized by reduced bone mass and degradation of bone microstructure. Mesenchymal stem cells (MSCs) have the potential to inhibit osteoporosis since they are multipotent stem cells that can differentiate into multiple types of cells including osteoblasts. Hence the mechanism of osteogenic differentiation of MSCs deserves comprehensive study. Here we report that KLF9 is a novel regulator in osteogenic differentiation of MSCs. We observed that depletion of KLF9 can largely compromise the osteogenic differentiation ability of MSCs. In addition, we revealed that inhibition of the PI3K-Akt pathway could also affect osteogenic differentiation since KLF9 depletion inhibits PI3K expression. Finally, we discovered that KLF9 expression can be induced by dexamethasone which is an essential component in osteogenic induction medium. Taken together, our study provides new insights into the regulatory role of KLF9 in osteogenic differentiation of MSCs.
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Diferenciación Celular , Factores de Transcripción de Tipo Kruppel , Células Madre Mesenquimatosas , Osteogénesis , Proteínas Proto-Oncogénicas c-akt , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Osteogénesis/genética , Diferenciación Celular/genética , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Dexametasona/farmacología , Células CultivadasRESUMEN
Human embryonic stem cells (hESCs) can proliferate infinitely (self-renewal) and give rise to almost all types of somatic cells (pluripotency). Hence, understanding the molecular mechanism of pluripotency regulation is important for applications of hESCs in regenerative medicine. Here we report that PATZ1 is a key factor that regulates pluripotency and metabolism in hESCs. We found that depletion of PATZ1 is associated with rapid downregulation of master pluripotency genes and prominent deceleration of cell growth. We also revealed that PATZ1 regulates hESC pluripotency though binding the regulatory regions of OCT4 and NANOG. In addition, we demonstrated PATZ1 is a key node in the OCT4/NANOG transcriptional network. We further revealed that PATZ1 is essential for cell growth in hESCs. Importantly, we discovered that depletion of PATZ1 drives hESCs to exploit glycolysis which energetically compensates for the mitochondrial dysfunction. Overall, our study establishes the fundamental role of PATZ1 in regulating pluripotency in hESCs. Moreover, PATZ1 is essential for maintaining a steady metabolic homeostasis to refine the stemness of hESCs.
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Células Madre Embrionarias Humanas , Células Madre Pluripotentes , Humanos , Células Madre Embrionarias Humanas/metabolismo , Células Madre Pluripotentes/metabolismo , Zinc , Secuencias AT-Hook , Diferenciación Celular/genética , Factores de Transcripción/metabolismo , Dedos de Zinc , Proteínas Represoras/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismoRESUMEN
INTRODUCTION: The high incidences of both the developmental delay among young children and the mental health problems of their caregivers are major threats to public health in low-income and middle-income countries. Parental training interventions during early childhood have been shown to benefit early development, yet evidence on strategies to promote caregiver mental health remains limited. In addition, evidence on the optimal design of scalable interventions that integrate early child development and maternal mental health components is scarce. METHODS AND ANALYSIS: We design a single-blind, factorial, cluster-randomised controlled, superiority trial that will be delivered and supervised by local agents of the All China Women's Federation (ACWF), the nationwide, government-sponsored social protection organisation that aims to safeguard the rights and interests of women and children. We randomise 125 villages in rural China into four arms: (1) a parenting stimulation arm; (2) a caregiver mental health arm; (3) a combined parenting stimulation and caregiver mental health arm and (4) a pure control arm. Caregivers and their children (aged 6-24 months at the time of baseline data collection) are selected and invited to participate in the 12-month-long study. The parenting stimulation intervention consists of weekly, one-on-one training sessions that follow a loose adaptation of the Reach Up and Learn curriculum. The caregiver mental health intervention is comprised of fortnightly group activities based on an adaptation of the Thinking Healthy curriculum from the WHO. Primary outcomes include measures of child development and caregiver mental health. Secondary outcomes include a comprehensive set of physical, psychological and behavioural outcomes. This protocol describes the design and evaluation plan for this programme. ETHICS AND DISSEMINATION: This study received approval from the Institutional Review Board of Stanford University (IRB Protocol #63680) and the Institutional Review Board of the Southwestern University of Finance and Economics in Chengdu, Sichuan, China. Informed oral consent will be obtained from all caregivers for their own and their child's participation in the study. The full protocol will be publicly available in an open-access format. The study findings will be published in economics, medical and public health journals, as well as Chinese or English policy briefs. TRIAL REGISTRATION NUMBER: AEA RCT Registry (AEARCTR-0010078) and ISRCTN registry (ISRCTN84864201).
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Cuidadores , Desarrollo Infantil , Niño , Humanos , Preescolar , Femenino , Cuidadores/psicología , Salud Mental , Método Simple Ciego , Gobierno , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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.
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Microbioma Gastrointestinal , Lacticaseibacillus casei , Lacticaseibacillus paracasei , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Probióticos , Humanos , Lacticaseibacillus , Enfermedad de Parkinson/tratamiento farmacológico , Estreñimiento/terapia , TirosinaRESUMEN
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.
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The self-esteem of students may be significantly associated with their academic performance. However, past research in developing contexts on this issue is limited, particularly among early adolescents. Using a sample of 3101 students from rural primary and junior high schools in China, this study measured their self-esteem by the Rosenberg Self-Esteem Scale (RSES) and explored its association with academic performance. Our findings indicate that students in rural China had both significantly lower self-esteem and a higher prevalence of low self-esteem when compared to past studies of similarly aged students both from urban China and internationally. Furthermore, there was a strong positive correlation between a student's self-esteem and academic performance. A one-SD increase in RSES score (indicating better self-esteem) was associated with an increase of 0.12 SD in standardized math scores (p < 0.001), and students with low self-esteem (RSES score < 25) scored lower on math tests by 0.14 SD (p < 0.001), which were robust and consistent when employing the propensity score matching method. Our study expands the growing body of empirical evidence on the link between self-esteem and academic performance among rural youth in developing countries and emphasizes the need to improve their self-esteem with the aim of helping them achieve academically.
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Rendimiento Académico , Autoimagen , Adolescente , Humanos , Anciano , Estudiantes , China/epidemiología , Población RuralRESUMEN
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.
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Enfermedad de Parkinson , Tirosina Descarboxilasa , Humanos , Tirosina Descarboxilasa/genética , Tirosina Descarboxilasa/metabolismo , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Estudios Transversales , Cromatografía Liquida , Antiparkinsonianos/uso terapéuticoRESUMEN
Behavioral strengths and difficulties among children and adolescents may be significantly associated with their academic performance; however, the evidence on this issue for rural youth in developing contexts is limited. This study explored the prevalence and correlates of mental health from three specific dimensions-internalizing problems, externalizing problems, and prosocial behavior-measured by the Strengths and Difficulties Questionnaire (SDQ), and the association of these dimensions with academic performance in math among a sample of 1500 students in rural China. Our findings indicated that students in rural China had worse behavioral difficulties and poorer prosocial skills when compared to most past studies conducted inside and outside of China. In addition, total difficulties and prosocial scores on the SDQ were significantly associated with student math test scores, as students whose externalizing, internalizing, and prosocial scores were in the abnormal range scored lower in math by 0.35 SD, 0.23 SD, and 0.33 SD, respectively. The results add to the growing body of empirical evidence related to the links between social environment, mental health, and academic performance in developing countries, highlighting the importance of students' mental health for their academic performance, and of understanding risk factors in the social environment among rural youth in developing countries.
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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.
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Enfermedad de Parkinson , Propionatos , Estreñimiento/etiología , Ácidos Grasos Volátiles/metabolismo , Heces/química , Humanos , Enfermedad de Parkinson/complicaciones , Propionatos/análisisRESUMEN
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.
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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.
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Autofagia/efectos de los fármacos , Ácido Butírico/farmacología , Epigénesis Genética/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Rotenona/toxicidad , Animales , Supervivencia Celular/efectos de los fármacos , Células PC12 , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , RatasRESUMEN
The outbreak of the COVID-19 epidemic has brought enormous impacts and changes to human mobility. To better understand and quantify the impacts of COVID-19 on city-wide ride-sourcing and taxi markets, we present exploratory evidence on the factors such as coronavirus cases related attributes, policy-related attributes, operational status of transportation, socio-economic status related variables, demographics related variables, and other factors. Based on 5-month real-world ride-sourcing and taxi datasets in Ningbo, China, including 37-million trips, we study the temporal variations of drivers' working characteristics and productivity of ride-sourcing and taxi fleets. The spatial heterogeneity of the impacts of COVID-19 on taxi and ride-sourcing trips is demonstrated in terms of traffic analysis zones (TAZs). Regression models are established to examine the impacts of a variety of explanatory variables, including COVID-19 related variables, on the district-level productivity of taxi and ride-sourcing services. The results show that the accumulated cured coronavirus cases, policy of closed management, operational status of mass transit, and average fee spent on transportation per capita significantly impact the productivity of the taxi and ride-sourcing fleets. This paper empirically reveals the influence of the epidemic on ride-sourcing and taxi markets and the temporal and spatial variations. The findings can support decision-making to restore the ride-sourcing and taxi markets and benefit other COVID-19 related research efforts.
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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.
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Hidrocarburos Clorados/sangre , Enfermedad de Parkinson/sangre , Plaguicidas/sangre , Anciano , Western Blotting , Estudios de Casos y Controles , Línea Celular Tumoral , Cognición/efectos de los fármacos , Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/inducido químicamente , Depresión/sangre , Depresión/inducido químicamente , Dieldrín/sangre , Dieldrín/toxicidad , Femenino , Hexaclorociclohexano/sangre , Hexaclorociclohexano/toxicidad , Humanos , Hidrocarburos Clorados/toxicidad , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Persona de Mediana Edad , Enfermedad de Parkinson/etiología , Plaguicidas/toxicidad , Propanil/sangre , Propanil/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Factores de RiesgoRESUMEN
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.
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Epigénesis Genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Complejo Represivo Polycomb 2 , ARN Largo no Codificante , Línea Celular Tumoral , Proliferación Celular/genética , Humanos , Leucocitos Mononucleares/metabolismo , Microglía/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
INTRODUCTION: Inadequate care during early childhood can lead to long-term deficits in skills. Parenting programmes that encourage investment in young children are a promising tool for improving early development outcomes and long-term opportunities in low-income and middle-income regions, such as rural China. METHODS: We conducted a systematic review and a meta-analysis to investigate the prevalence of early developmental delays and stimulating parenting practices as well as the effect of parental training programmes on child development outcomes in rural China. We obtained data in English from EconPapers, PubMed, PsycARTICLES, Cochrane Library, Web of Science and Scopus (Elsevier) and in Chinese from China National Knowledge Infrastructure, Wanfang Data and VIP Information. We conducted frequentist meta-analyses of aggregate data and estimated random-effects meta-regressions. Certainty of evidence was rated according to the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: We identified 19 observational studies on the prevalence of developmental delays and stimulating parenting practices for children under 5 years of age (n=19 762) and ten studies on the impact of parental training programmes on early child development (n=13 766). Children's risk of cognitive, language and social-emotional delays in the rural study sites (covering 14 provinces mostly in Central and Western China) was 45%, 46%, and 36%, respectively. Parental training programmes had a positive impact on child cognition, language and social-emotional development. CONCLUSION: There is evidence to suggest that early developmental delay and the absence of stimulating parenting practices (ie, reading, storytelling and singing with children) may be prevalent across rural, low-income and middle-income regions in Central and Western China. Results support the effectiveness of parental training programmes to improve early development by encouraging parental engagement. TRIAL REGISTRATION NUMBER: This study was registered with PROSPERO (CRD42020218852).
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Desarrollo Infantil , Responsabilidad Parental , Niño , Preescolar , China/epidemiología , Humanos , Padres , Población RuralRESUMEN
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.
Asunto(s)
Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Diagnóstico Diferencial , Ácidos Grasos Volátiles , Humanos , Atrofia de Múltiples Sistemas/diagnóstico , Enfermedad de Parkinson/diagnóstico , PropionatosRESUMEN
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.
RESUMEN
Objective: Levodopa up-titration is the primary therapeutic strategy as the Parkinson's disease (PD) progresses. However, the effects of levodopa up-titration on blood pressure (BP) are inconclusive. This study aimed to investigate the effect of acute levodopa up-titration simulated by levodopa challenge test (LCT) on BP in patients with early stage PD. Methods: We monitored BP in 52 patients with early stage PD using a standardized standing test. BP was assessed in supine position after 10 min of rest and at 1 and 3 min after standing up. BP was measured in the "off-state" and the best "on-state" during LCT in the morning at hospital. In another day, "off-state" and the best "on-state" BP was measured before and after anti-PD drug uptake in the morning at home. Demographic and clinical features of the patients were evaluated and analyzed. Results: In the LCT, the prevalence of OH in the "off-state" and the best "on-state" was 11.5 and 13.5%, respectively. Additionally, the OH in the best "on-state" was associated with OH in the "off-state" and monoamine oxidase B inhibitor use. Although 38 (73.1%) patients experienced levodopa-induced hypotension during the LCT, no risk factors were identified. While BP reductions were observed after taking anti-PD drugs at home, no further reduction was seen during acute levodopa up-titration simulated by the LCT. Conclusion: Our results demonstrate that acute levodopa up-titration does not exacerbate BP reduction induced by anti-PD drugs at home. BP monitoring is critical for the management of patients with PD.