High expression of COPZ2 is associated with poor prognosis and cancer progression in glioma.

Background: Coatomer protein complex zeta 2 (COPZ2) is a member of heptameric coatomer protein complex I and has been reported to be involved in various tumors. However, COPZ2's potential involvement in glioma remains to be explored. Methods: The COPZ2 expression and related clinical data were obtained from The Cancer Genome Atlas (TCGA). TIMER2.0 and the Ualcan database were utilized to assess the COPZ2 expression in various tumors. Univariable, multivariate Cox regression, Kaplan-Meier methods, nomogram analysis, and ROC curve analysis were carried out to assess the relationship of COPZ2 and other prognostic factors with glioma. The LinkedOmics database was used to predict the potential biological mechanism of COPZ2 in glioma. We also conducted in vitro experiments to evaluate the functional role and mechanism of COPZ2 in glioma cell lines. Results: We found that COPZ2 was highly expressed in glioma and it was associated with age and WHO grades. Kaplan-Meier survival curves, Cox analysis, nomogram analysis, and ROC curve showed that COPZ2 was a disadvantageous factor in poor glioma prognosis. The functions of COPZ2 and co-expression genes were significantly associated with neutrophil-mediated immunity, granulocyte activation, and response to interferon-gamma. In addition, COPZ2 knockdown significantly inhibited the proliferation, migration, and invasion of glioblastoma cells. Mechanistically, COPZ2 suppressed tumor development by participating in the regulation of the PI3K-AKT signaling pathway. Conclusion: Our results demonstrated that the elevation of COPZ2 was associated with the prognosis and progression of glioma, and it might be a potential diagnostic and prognostic biomarker for glioma.

Reviving: restoring depression-like behaviour through glial cell-derived neurotrophic factor treatment in the medial prefrontal cortex.

BACKGROUND: Depression is a prevalent nonmotor symptom in Parkinson disease and can greatly reduce the quality of life for patients; the dopamine receptors found in glutamatergic pyramidal cells in the medial prefrontal cortex (mPFC) play a role in regulating local field activity, which in turn affects behavioural and mood disorders. Given research showing that glial cell-derived neurotrophic factor (GDNF) may have an antidepressant effect, we sought to evaluate the impact of exogenous GDNF on depression-like behaviour in mouse models of Parkinson disease. METHODS: We used an established subacute model of Parkinson disease in mice involving intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by brain stereotaxic injection of GDNF into the mPFC region. Subsequently, we assessed depression-like behaviour using the sucrose preference test, forced swimming test and tail suspension test, while also evaluating protein expression in the mPFC. RESULTS: We included 60 mice, divided into 3 groups, including a control group (saline injection), an MPTP plus saline injection group and an MPTP plus GDNF injection group. We found that exogenous GDNF injection into the mPFC led to an increase in dopamine receptor D1 (DRD1) protein levels. We also observed that activating the protein kinase A pathway through DRD1 produced a prolonged antidepressant response. Under GDNF stimulation, the expression of dopamine receptor D2 (DRD2) remained constant, suggesting that the DRD2 signal was ineffective in alleviating depression-like symptoms. Moreover, our investigation involved Golgi staining and Western blot techniques, which found enhanced synaptic plasticity, including increased dendritic branches, dendritic spines and retrograde protection after GDNF treatment in Parkinson disease models. LIMITATIONS: A subtle motor phenotype became evident only toward the conclusion of the behavioural testing period. The study exclusively involved male mice, and no separate control group receiving only GDNF treatment was included in the experimental design. CONCLUSION: Our findings support a positive effect of exogenous GDNF on synaptic plasticity, mediated by DRD1 signalling in the mPFC, which could facilitate depression remission in Parkinson disease.

Distinct serum GDNF coupling with brain structural and functional changes underlies cognitive status in Parkinson's disease.

AIM: Aberrations in brain connections are implicated in the pathogenesis of Parkinson's disease (PD). We previously demonstrated that Glial cell-derived neurotrophic factor (GDNF) reduction is associated with cognition decline. Nonetheless, it is elusive if the pattern of brain topological connectivity differed across PD with divergent serum GDNF levels, and the accompanying profile of cognitive deficits has yet to be determined. METHODS: We collected data on the participants' cognition, demographics, and serum GDNF levels. Participants underwent 3.0T magnetic resonance imaging, and we assessed the degree centrality, brain network topology, and cortical thickness of the healthy control (HC) (n = 25), PD-high-GDNF (n = 19), and PD-low-GDNF (n = 19) groups using graph-theoretic measures of resting-state functional MRI to reveal how much brain connectivity varies and its clinical correlates, as well as to determine factors predicting the cognitive status in PD. RESULTS: The results show different network properties between groups. Degree centrality abnormalities were found in the right inferior frontal gyrus and right parietal lobe postcentral gyrus, linked with cognition scores. The two aberrant clusters serve as a potentially powerful signal for determining whether a patient has PD and the patient's cognition level after integrating with GDNF, duration, and dopamine dosage. Moreover, we found a significant positive relationship between the thickness of the left caudal middle frontal lobe and a plethora of cognitive domains. Further discriminant analysis revealed that the cortical thickness of this region could distinguish PD patients from healthy controls. The mental state evaluation will also be more precise when paired with GDNF and duration. CONCLUSION: Our findings reveal that the topological features of brain networks and cortical thickness are altered in PD patients with cognitive deficits. The above change, accompanied by the serum GDNF, may have merit as a diagnosis marker for PD and, arguably, cognition status.

Urinary neonicotinoids and metabolites are associated with obesity risk in Chinese school children.

BACKGROUND: Neonicotinoids are the most widely used insecticides. Laboratory studies have suggested that neonicotinoids are one potential obesogen, but relevant data are limited in human. OBJECTIVE: To examine the association between exposure to neonicotinoids and childhood obesity. METHODS: We investigated 442 children in Shanghai, East China and measured eight neonicotinoids (thiamethoxam, clothianidin, acetamiprid, imidacloprid, thiacloprid, nitenpyram, dinotefuran, and imidaclothiz) and four metabolites (N-desmethyl-thiamethoxam, N-desmethyl-clothianidin, N-desmethyl-acetamiprid, and 5-OH-imidacloprid) in urine. Body mass index (BMI) and waist circumference (WC) were used to identify general overweight/obesity and central obesity, respectively. Linear and logistic regression models based on generalized estimating equations were used to investigate the associations of urinary neonicotinoids and metabolites with BMI z-score, WC z-score, general overweight/obesity, and central obesity. RESULTS: Children with a positive detection of clothianidin and its metabolite had a marginally higher BMI z-score (regression coefficient (ß): 0.08, 95% confidence interval (95% CI): 0.01, 0.14) after adjusted for relevant covariates. After creatinine-adjusted concentration was trichotomized, compared to children with a negative detection, children in the high urinary concentration of acetamiprid and its metabolite had a low BMI z-score (ß: -0.19, 95%CI: -0.30, -0.08), children in the medium urinary concentration of neonicotinoids and metabolites other than thiamethoxam, clothianidin, acetamiprid, and their metabolites had a marginally higher BMI z-score (ß: 0.25, 95%CI: 0.03, 0.46), a higher WC z-score (ß: 0.24, 95%CI: 0.14, 0.33), and a higher odds of central obesity (odds ratio (OR): 2.16, 95% CI: 1.28, 3.63), and children in the medium urinary concentration of all neonicotinoids and metabolites had a higher odds of central obesity (OR: 1.55, 95%CI: 1.04, 2.33). Some associations showed sex- and age- related differences. CONCLUSION: Urinary neonicotinoids and metabolites were found to be differently associated with obesity-related indexes, which suggested that exposure to neonicotinoids might have a mixed effect on childhood obesity.

Dopamine in the prefrontal cortex plays multiple roles in the executive function of patients with Parkinson's disease.

Parkinson's disease can affect not only motor functions but also cognitive abilities, leading to cognitive impairment. One common issue in Parkinson's disease with cognitive dysfunction is the difficulty in executive functioning. Executive functions help us plan, organize, and control our actions based on our goals. The brain area responsible for executive functions is called the prefrontal cortex. It acts as the command center for the brain, especially when it comes to regulating executive functions. The role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called dopamine. However, little is known about how dopamine affects the cognitive functions of patients with Parkinson's disease. In this article, the authors review the latest research on this topic. They start by looking at how the dopaminergic system, is altered in Parkinson's disease with executive dysfunction. Then, they explore how these changes in dopamine impact the synaptic structure, electrical activity, and connection components of the prefrontal cortex. The authors also summarize the relationship between Parkinson's disease and dopamine-related cognitive issues. This information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson's disease.

Sprouting of afferent and efferent inputs to pelvic organs after spinal cord injury.

Neural plasticity occurs within the central and peripheral nervous systems after spinal cord injury (SCI). Although central alterations have extensively been studied, it is largely unknown whether afferent and efferent fibers in pelvic viscera undergo similar morphological changes. Using a rat spinal cord transection model, we conducted immunohistochemistry to investigate afferent and efferent innervations to the kidney, colon, and bladder. Approximately 3-4 weeks after injury, immunostaining demonstrated that tyrosine hydroxylase (TH)-labeled postganglionic sympathetic fibers and calcitonin gene-related peptide (CGRP)-immunoreactive sensory terminals sprout in the renal pelvis and colon. Morphologically, sprouted afferent or efferent projections showed a disorganized structure. In the bladder, however, denser CGRP-positive primary sensory fibers emerged in rats with SCI, whereas TH-positive sympathetic efferent fibers did not change. Numerous CGRP-positive afferents were observed in the muscle layer and the lamina propria of the bladder following SCI. TH-positive efferent inputs displayed hypertrophy with large diameters, but their innervation patterns were sustained. Collectively, afferent or efferent inputs sprout widely in the pelvic organs after SCI, which may be one of the morphological bases underlying functional adaptation or maladaptation.

Comprehensive Analysis of the miRNA-mRNA Pathological Regulatory Network of Intestinal CD4 + T Cells in Parkinson's Disease.

Infiltration of CD4 + T cells was found in brain tissue samples from PD patients, suggesting their involvement in developing central nervous system (CNS) disease. The idea of the gut-brain axis further corroborates intestinal T cells' activation as the central immune response initiation. However, the specific factors and molecular pathways regulating intestinal T-cell activation are unclear. We used the GSE156287 and GSE145814 datasets from the GEO database to analyze and obtain the miRNAs, which are aberrantly expressed in intestinal CD4 + T cells in PD patients and predict their regulatory target mRNAs. Further, combined with the GSE174473 dataset of CD4 + T cells sequencing in PD patients, we finally clarified the aberrant genes expressed in CD4 + T cells from the intestine of PD patients and constructed a miRNA-mRNA regulatory network. The highlight of our findings showed pathways, networks, biological functions, and key molecules potentially involved in the miRNA-mediated functional effects in CD4 + T cell from the intestine of PD patients. The hsa-miR-3180-3p mediated CBX8, etc. were determined as most effective in enhancing T cell survival. PEG10, etc. regulated by hsa-miR-20a-3p targets were possibly involved in T cell differentiation. The JPT2 regulated by hsa-miR-1281 were involved in influencing T cell infiltration. The discovery of this interaction between miRNA and mRNA in CD4 + T cell has important implications for understanding the intestinal initial of PD pathological molecular and anti-inflammation of T cell activation.

Treadmill Exercise Alleviates Cognition Disorder by Activating the FNDC5: Dual Role of Integrin αV/ß5 in Parkinson's Disease.

Parkinson's disease with cognitive impairment (PD-CI) results in several clinical outcomes for which specific treatment is lacking. Although the pathogenesis of PD-CI has not yet been fully elucidated, it is related to neuronal plasticity decline in the hippocampus region. The dopaminergic projections from the substantia nigra to the hippocampus are critical in regulating hippocampal plasticity. Recently, aerobic exercise has been recognized as an effective therapeutic strategy for enhancing plasticity through the secretion of various muscle factors. The exact role of FNDC5-an upregulated, newly identified myokine produced after exercise-in mediating hippocampal plasticity and regional dopaminergic projections in PD-CI remains unclear. In this study, the effect of treadmill exercise on hippocampal synaptic plasticity was evaluated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced chronic PD models. The results showed that treadmill exercise substantially alleviated the motor dysfunction, cognition disorder, and dopaminergic neuron degeneration induced by MPTP. Here, we discovered that the quadriceps, serum, and brain FNDC5 levels were lower in PD mice and that intervention with treadmill exercise restored FNDC5 levels. Moreover, treadmill exercise enhanced the synaptic plasticity of hippocampal pyramidal neurons via increased dopamine levels and BDNF in the PD mice. The direct protective effect of FNDC5 is achieved by promoting the secretion of BDNF in the hippocampal neurons via binding the integrin αVß5 receptor, thereby improving synaptic plasticity. Regarding the indirect protection effect, FNDC5 promotes the dopaminergic connection from the substantia nigra to the hippocampus by mediating the interaction between the integrin αVß5 of the hippocampal neurons and the CD90 molecules on the membrane of dopaminergic terminals. Our findings demonstrated that treadmill exercise could effectively alleviate cognitive disorders via the activation of the FNDC5-BDNF pathway and enhance the dopaminergic synaptic connection from SNpc to the hippocampus in the MPTP-induced chronic PD model.

Amphiregulin blockade decreases the levodopa-induced dyskinesia in a 6-hydroxydopamine Parkinson's disease mouse model.

BACKGROUND: Levodopa (L-DOPA) is considered the most reliable drug for treating Parkinson's disease (PD) clinical symptoms. Regrettably, long-term L-DOPA therapy results in the emergence of drug-induced abnormal involuntary movements (AIMs) in most PD patients. The mechanisms underlying motor fluctuations and dyskinesia induced by L-DOPA (LID) are still perplexing. METHODS: Here, we first performed the analysis on the microarray data set (GSE55096) from the gene expression omnibus (GEO) repository and identified the differentially expressed genes (DEGs) using linear models for microarray analysis (Limma) R packages from the Bioconductor project. 12 genes (Nr4a2, Areg, Tinf2, Ptgs2, Pdlim1, Tes, Irf6, Tgfb1, Serpinb2, Lipg, Creb3l1, Lypd1) were found to be upregulated. Six genes were validated on quantitative polymerase chain reaction and subsequently, Amphiregulin (Areg) was selected (based on log2 fold change) for further experiments to unravel its involvement in LID. Areg LV_shRNA was used to knock down Areg to explore its therapeutic role in the LID model. RESULTS: Western blotting and immunofluorescence results show that AREG is significantly expressed in the LID group relative to the control. Dyskinetic movements in LID mice were alleviated by Areg knockdown, and the protein expression of delta FOSB, the commonly attributable protein in LID, was decreased. Moreover, Areg knockdown reduced the protein expression of P-ERK. In order to ascertain whether the inhibition of the ERK pathway (a common pathway known to mediate levodopa-induced dyskinesia) could also impede Areg, the animals were injected with an ERK inhibitor (PD98059). Afterward, the AIMs, AREG, and ERK protein expression were measured relative to the control group. A group treated with ERK inhibitor had a significant decrease of AREG and phosphorylated ERK protein expression relative to the control group. CONCLUSION: Taken together, our results indicate unequivocal involvement of Areg in levodopa-induced dyskinesia, thus a target for therapy development.

Blunt dopamine transmission due to decreased GDNF in the PFC evokes cognitive impairment in Parkinson's disease.

Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson's disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson's disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson's disease. We then established a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson's disease.

Association between alcohol related knowledge, attitude,practice and alcohol use disorder among high school students / 中国学校卫生

Objective@#To analyze the relationship between alcohol related knowledge, attitude,practice and alcohol use disorder among high school students, and to provide reference for alcohol abuse intervention.@*Methods@#The study adopted stratified cluster sampling. A total of 811 high school students from 4 high schools in Changning District were selected to conduct a questionnaire survey on alcohol related knowledge, attitude,practice and alcohol dependence. The software SPSS 20.0 was used for statistical analysis.@*Results@#There were 279 (34.4%) high school students with mild alcohol use disorder and 29 (3.6%) with severe alcohol use disorder. The average score of high school students alcohol related knowledge, attitude,practice scores were (9.56±3.55) ( 4.96± 2.36) and (2.81±1.29),respectively. High school students alcohol related knowledge, attitude,practice were negatively correlated with alcohol use disorder score ( r =-0.10, -0.39, -0.71, P <0.01). Multivariate Logistic regression indicated that the total score of alcohol related KAP ( OR=0.86, 95%CI =0.83-0.89) and the family economic level (high level: OR=2.05, 95%CI =1.26-3.32) were positively associated with mild alcohol use disorder. The total score of alcohol related KAP ( OR=0.76, 95%CI =0.70-0.83) and school type ( OR=3.72, 95%CI =1.51-9.18) were positively associated with severe alcohol use disorder ( P <0.05).@*Conclusion@#There is a correlation between low alcohol related KAP and alcohol use disorder, alcohol related health education should be strengthened, especially among vocational school students and students from high family economic level.

Susceptibility of cytoskeletal-associated proteins for tumor progression.

The traditional functions of cytoskeletal-associated proteins (CAPs) in line with polymerization and stabilization of the cytoskeleton have evolved and are currently underrated in oncology. Although therapeutic drugs have been developed to target the cytoskeletal components directly in cancer treatment, several recently established therapeutic agents designed for new targets block the proliferation of cancer cells and suppress resistance to existing target agents. It would seem like these targets only work toward inhibiting the polymerization of cytoskeletal components or hindering mitotic spindle formation in cancer cells, but a large body of literature points to CAPs and their culpability in cell signaling, molecular conformation, organelle trafficking, cellular metabolism, and genomic modifications. Here, we review those underappreciated functions of CAPs, and we delineate the implications of cellular signaling instigated by evasive properties induced by aberrant expression of CAPs in response to stress or failure to exert normal functions. We present an analogy establishing CAPs as vulnerable targets for cancer systems and credible oncotargets. This review establishes a paradigm in which the cancer machinery may commandeer the conventional functions of CAPs for survival, drug resistance, and energy generation; an interesting feature overdue for attention.

PIG-A gene mutation as a genotoxicity biomaker in polycyclic aromatic hydrocarbon-exposed barbecue workers.

BACKGROUND: The PIG-A gene mutation assay is a valuable tool for measuring in vivo gene mutations in blood cells. The human PIG-A assay, used as a potential genotoxicity biomarker, is minimally invasive, sensitive, and cost-efficient; however, the relationship between carcinogen exposure and PIG-A mutations is not well understood. METHODS: We investigated the genotoxic effect of red blood cells using PIG-A assay and lymphocyte cytokinesis-block micronucleus test in barbecue restaurant workers (N = 70) exposed to polycyclic aromatic hydrocarbons (PAHs) and self-identified healthy control subjects (N = 56). Urinary PAH metabolites were measured to evaluate internal exposure levels. RESULTS: Multivariate Poisson regression showed that the PAH-exposed workers exhibited significantly higher PIG-A mutant frequency (MF) (8.04 ± 6.81 × 10- 6) than did the controls (5.56 ± 5.26 × 10- 6) (RR = 0.707, 95% CI: 0.615-0.812, P < 0.001). These results indicate that PAH exposure is a risk factor for elevated PIG-A MF. The frequencies of micronuclei (MN) and nuclear buds (NBUD) in the PAH-exposed workers (MN: 3.06 ± 2.07 ‰, NBUD: 1.38 ± 1.02 ‰) were also significantly higher than in the controls (MN: 1.46 ± 0.64 ‰, P < 0.001; NBUD: 0.70 ± 0.60 ‰, P < 0.001). Additionally, PIG-A MFs showed better associations with several urinary hydroxylated PAH metabolites (P2-OH-Flu = 0.032, r2-OH-Flu = 0. 268; P2-OH-Phe = 0.022, r2-OH-Phe = 0.286; P3-OH-Phe = 0.0312, r3-OH-Phe = 0.270; P4-OH-Phe = 0.018, r4-OH-Phe = 0.296), while the increase in MN, NPB, and NBUD frequencies was not associated with any OH-PAH metabolites; and high-PAH-exposed workers showed the highest PIG-A MFs. Furthermore, there was a significant association between PIG-A MF and PAH exposure levels (Chi-square test for trend, P = 0.006). CONCLUSIONS: Our results indicate that an increase in PIG-A MF in barbecue workers could reflect the response to PAH exposure, providing evidence of its potential as a genotoxicity biomarker in human risk assessment.

Urinary antibiotic level of school children in Shanghai, East China, 2017-2020.

In recent years, an extensive exposure to antibiotics from various sources has been demonstrated in China by the biomonitoring method, but the temporal trend remains little known. The study aim was to explore the temporal trend of exposure to antibiotics and associated health risk in children. A dynamic child cohort was established in Shanghai, East China between 2017 and 2020. A total of 684 school children aged 7-11 years were included, and 280 in 2017, 279 in 2018, 288 in 2019, and 287 in 2020 participated in annual surveys. Twenty-three typical antibiotics and three metabolites from five categories (four tetracyclines, five qinolones, six macrolides, eight sulfonamides, and three phenicols), bisphenol A (BPA), and monobutyl phthalate (MBP) were determined in urine. Logistic regression analysis with generalized estimating equations was conducted to investigate the associations between various variables and the detection frequency of antibiotics in urine. Seventeen antibiotics and three metabolites were found in 51.9% of all urine samples. Compared to 2017, the detection frequency in urine reduced 31.8% in 2020 for all antibiotics (58.2% vs 39.7%) and reduced 36.8%-55.8% for tetracyclines (11.4% vs 7.0%), qinolones (34.3% vs 21.3%), macrolides (8.6% vs 3.8%), sulfonamides (16.4% vs 8.7%), and phenicols (19.3% vs 12.2%). After accounting for personal characteristics, food consumption, and urinary BPA and MBP, a decreasing temporal trend of detection frequencies was observed from 2017 to 2020 for most antibiotics. Urinary concentration, estimated daily intake, and acceptable daily intake-based health risk of antibiotics showed a temporal trend similar to detection frequency. There was an extensive exposure to antibiotics in children. However, a decreasing temporal trend occurred for the exposure during the period from 2017 to 2020. The trend was likely to be caused by decreased antibiotic use and/or decreased residues in food and/or drinking water.

Association of triclosan and triclocarban in urine with obesity risk in Chinese school children.

BACKGROUND: Laboratory studies have suggested that triclosan and triclocarban can influence energy metabolism by multiple mechanisms and are potential obesogens, but the effect on obesity risk has not been well investigated in human. OBJECTIVE: To examine the associations of triclosan and triclocarban in urine with childhood obesity. METHODS: We investigated 458 school children aged 7-11 years who entered a dynamic cohort of children established in Shanghai in 2019 and 2020. Triclosan and triclocarban were determined in first morning urine by liquid chromatography coupled to mass spectrometry. Body mass index (BMI) and waist circumference (WC) were used to identify general overweight/obesity and central obesity, respectively. Logistic regression and linear models of generalized estimating equations (GEE) were used to investigate the association between urinary triclosan and triclocarban with obesity prevalence. RESULTS: After adjusting for potential confounders, children with detectable triclocarban in urine had a higher proportion of general overweight/obesity (odds ratio (OR): 1.84; 95% confidential interval (95% CI): 1.19, 2.85) or central obesity (OR: 1.71; 95% CI: 1.03, 2.84). Compared to the low tertile, children in the median tertile of triclosan showed a higher proportion of central obesity (OR: 1.78; 95 %CI: 0.98, 3.24) and children in the high tertile of triclocarban had a higher proportion of general overweight/obesity (OR: 2.25; 95 %CI: 1.31, 3.88) and central obesity (OR: 2.08; 95 %CI: 1.12, 3.87). When the tertiles of triclocarban in urine were treated as a continuous variable, a positive exposure-response relationship was found with general overweight/obesity (OR: 1.50; 95 %CI: 1.15, 1.96) and central obesity (OR: 1.44; 95 %CI: 1.06, 1.95). Multiple linear regression showed a positive exposure-response relationship between triclocarban and BMI (ß: 0.45; 95 %CI: 0.11, 0.80) values. CONCLUSION: Exposure to triclosan and triclocarban was associated with increased risk of childhood obesity. Given the cross-sectional design, more studies are needed to interrogate these findings.

Treadmill exercise alleviates neuronal damage by suppressing NLRP3 inflammasome and microglial activation in the MPTP mouse model of Parkinson's disease.

Treadmill exercise has been recognized as an effectively therapeutic strategy for Parkinson's disease (PD). However, its exact molecular mechanism of promoting PD remain unclear. Recently, the NLRP3 inflammasome is considered to play a critical role in the pathogenesis of PD. In this study, we investigated whether NLRP3 inflammasome was involved in treadmill exercise-induced neuroprotection and anti-inflammation effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. 8-week-old male mice (C57BL/6 strain) were divided into four groups: Control, MPTP, MPTP + EX and EX. MPTP was intraperitoneally injected into mice to establish chronic PD model. The open-field test and pole test were used to assess motor function. The results showed that treadmill exercise significantly alleviated motor dysfunction and dopaminergic neuron degeneration induced by MPTP. In addition, we also found that treadmill exercise suppressed MPTP-triggered microglia activation and the co-localization of NLRP3+/Iba-1+ cells in the substantia nigra. These effects were associated with suppression NLRP3 inflammasome via down-regulation of TLR4/MyD88/NF-κB pathway. Overall, our study demonstrated that treadmill exercise could effectively alleviates neuronal damage via inhibition of NLRP3 inflammasome and microglial activation in MPTP-induced PD mouse model.

Smarcd1 antagonizes the apoptosis of injured MES23.5 DA cells by enhancing the effect of Six2 on GDNF expression.

Glial cell line-derived neurotrophic factor (GDNF) played critical roles in the survival and repair of dopaminergic (DA) neurons. Transcription factor Six2 could repair injured DA cells by promoting the expression of GDNF, however, the underlying molecular mechanisms remain largely unknown. In this study, we screened forty-three proteins that interacted with Six2 in MES23.5 DA cells treated with 6-OHDA by liquid chromatography - electrospray - ionization tandem mass spectrometry (LC-ESI-ITMS/MS). Among these proteins, Smarcd1 is a member of SWI/SNF chromatin-remodeling complex family. Our results confirmed that Smarcd1 formed a transcription complex with Six2, and Smarcd1 mainly binded to the 2840 bp-2933 bp region of the GDNF promoter. Furthermore, knockdown of Smarcd1 inhibited the effect of Six2 on GDNF expression, and resulted in decreased cell viability and increased the apoptosis of injured DA neurons, and the result of overexpression of Smarcd1 is opposite to knockdown. Taken together, our results indicate that smarcd1 can be recruited to the promoter region of GDNF by transcription factor Six2 to promote the effect of Six2 on GDNF expression and protect injured MES23.5 DA cells, which could be useful in identifying potential drug targets for promoting endogenous GDNF expression.

Deciphering Spinal Endogenous Dopaminergic Mechanisms That Modulate Micturition Reflexes in Rats with Spinal Cord Injury.

Spinal neuronal mechanisms regulate recovered involuntary micturition after spinal cord injury (SCI). It was recently discovered that dopamine (DA) is synthesized in the rat injured spinal cord and is involved in lower urinary tract (LUT) activity. To fully understand the role of spinal DAergic machinery in micturition, we examined urodynamic responses in female rats during pharmacological modulation of the DA pathway. Three to four weeks after complete thoracic SCI, the DA precursor L-DOPA administered intravenously during bladder cystometrogram (CMG) and external urethral sphincter (EUS) electromyography (EMG) reduced bladder overactivity and increased the duration of EUS bursting, leading to remarkably improved voiding efficiency. Apomorphine (APO), a non-selective DA receptor (DR) agonist, or quinpirole, a selective DR2 agonist, induced similar responses, whereas a specific DR2 antagonist remoxipride alone had only minimal effects. Meanwhile, administration of SCH 23390, a DR1 antagonist, reduced voiding efficiency by increasing tonic EUS activity and shortening the EUS bursting period. Unexpectedly, SKF 38393, a selective DR1 agonist, increased EUS tonic activity, implying a complicated role of DR1 in LUT function. In metabolic cage assays, subcutaneous administration of quinpirole decreased spontaneous voiding frequency and increased voiding volume; L-DOPA and APO were inactive possibly because of slow entry into the CNS. Collectively, tonically active DR1 in SCI rats inhibit urine storage and enhance voiding by differentially modulating EUS tonic and bursting patterns, respectively, while pharmacologic activation of DR2, which are normally silent, improves voiding by enhancing EUS bursting. Thus, enhancing DA signaling achieves better detrusor-sphincter coordination to facilitate micturition function in SCI rats.

Comprehensive serum metabolic and proteomic characterization on cognitive dysfunction in Parkinson's disease.

BACKGROUND: Given the increased incidence of Parkinson's disease (PD) and the lack of accurate early diagnosis of PD with cognitive impairment (PD-CI), we compared the serum metabolomes and proteomes of 26 patients with PD without cognitive impairment (PD-N) and 31 patients with PD-CI by combining grade-dependent proteomics and metabolomics analyses. METHODS: Logistic and linear regression analyses were performed for differential metabolic indicators, cognition, and clinical diagnosis. Ingenuity pathway analysis (IPA) was used to identify metabolites linked to different pathways. Bioinformatics revealed 16 differentially expressed proteins and 32 metabolites. RESULTS: The positive metabolic indicators related to the differential proteins were one sphingolipid, five phosphatidylcholines, and five long-chain fatty acids. The obtained metabolic and proteomics IPA network highlighted the central term of this network was inflammation and abnormal lipid metabolism which are prominent in PD-CI. There was a strong negative correlation between the Mini-Mental State Examination (MMSE)score and LPC (18:1). The receiver operating characteristic (ROC) of LPC (18:1) for PD-N and PD-CI showed that the area under the curve (AUC) value was 0.660 (P=0.039). CONCLUSIONS: In conclusion, serum LPC (18:1) is inversely linked to cognition in PD and presented its potential clinical value in distinguishing the presence or absence of cognitive impairment in PD. The deeper implication of our discovery indicates abnormal lipid metabolism is associated with changes of cognitive status and suggests the potential for possibility of immune system- inflammatory involvement.

Lower GDNF Serum Level Is a Possible Risk Factor for Constipation in Patients With Parkinson Disease: A Case-Control Study.

Background: Constipation is a significant symptom of Parkinson's disease (PD). Glial-derived neurotrophic factor (GDNF) is important for the morphogenesis of the enteric nervous system and plays a critical role in the preservation of mucosal integrity under enteric glia surveillance. The aim of this work was to evaluate the serum levels of GDNF in patients with PD with and without constipation. Methods: This work included 128 patients with PD. The patients were classified into three groups: those with PD but no constipation (nCons-PD) (n = 49), those with prodromal stage constipation (Cons-Pro-PD) (n = 48), and those with clinical stage constipation (Cons-Clinic-PD) (n = 31). The association between serum GDNF concentration and constipation was explored using logical regression. Results: The nCons-PD group's mean GDNF levels were 528.44 pg/ml, which was higher than the Cons-Pro-PD group's 360.72 pg/ml and the Cons-Clinic-PD group's 331.36 pg/ml. The results of binary logistic regression indicated that GDNF was a protective factor in the prevention of constipation. Cons-Clinic-PD group had a higher score of MDS-UPDRS-II, MDS-UPDRS-III, MDS-UPDRS-IV, and a higher H-Y staging as compared with nCons-PD group. Relative to the nCons-PD group, Cons-Clinic-PD had higher NMSS scores, lower MoCA and PDSS scores, and were more likely to have RBD. Conclusions: GDNF serum levels are lower in patients with PD who are constipated. A low GDNF level is a potential risk factor for constipation in patients with PD.