Olfactory Dysfunction and Long-Term Trajectories of Sleep Disorders among early Parkinson's Disease: Findings from a Longitudinal Cohort.

BACKGROUND: Previous studies have suggested a connection between impaired olfactory function and an increased risk of rapid eye movement sleep behavior disorder (RBD) in individuals diagnosed with Parkinson's disease (PD). However, there is a gap in knowledge regarding the potential impact of olfactory dysfunction on the long-term patterns of sleep disorders among early PD patients. METHODS: Data from the Parkinson's Progression Markers Initiative program included 589 participants with assessments of sleep disorders using the Epworth Sleepiness Scale (ESS) and RBD Screening Questionnaire (RBDSQ). Olfactory dysfunction at baseline was measured using the University of Pennsylvania Smell Identification Test. Trajectories of sleep disorders over a 5-year follow-up were identified using group-based trajectory modeling, and the relationship between olfactory dysfunction and sleep disorder trajectories was examined through binomial logistic regression. RESULTS: Two distinct trajectories of sleep disorders over the 5-year follow-up period were identified, characterized by maintaining a low or high ESS score and a low or high RBDSQ score. An inversion association was observed between olfactory function measures and trajectories of excessive daytime sleepiness (odds ratio [OR] = 0.97, 95% confidence interval [CI] 0.95, 1.00, p = 0.038), after controlling for potential covariates. Similarly, olfactory function showed a significant association with lower trajectories of probable RBD (OR = 0.96, 95% CI 0.94, 0.98, p = 0.001) among early PD individuals. Consistent findings were replicated across alternative analytical models. CONCLUSIONS: Our findings indicated that olfactory dysfunction was associated with unfavorable long-term trajectories of sleep disorders among early PD.

A natural compound melatonin enhances the effects of Nimotuzumab via inhibiting EGFR in glioblastoma.

Sleep disorders are prevalent and debilitating symptoms in primary brain tumor patients, notably those receiving radiation therapy. Nevertheless, the relationship between sleep disorders, melatonin - a circadian rhythm regulatory hormone, and gliomas is underexplored. Melatonin exhibits various biological functions, one of them being anti-tumor activity. In the context of gliomas, often overexpressing EGFR, the humanized monoclonal antibody Nimotuzumab targets this marker. Our research discovered that variations in circadian rhythm significantly influence tumor growth in mice through impacting melatonin secretion. Harnessing proteogenomic, we identified that melatonin could inhibit the phosphorylation of EGFR and its downstream effectors, key elements in angiogenesis and tumor progression. Building on structural simulations, we propose that melatonin may amplify Nimotuzumab's anti-glioma efficacy by inhibiting EGFR TK dimerization. This proposition was validated in our in vitro and in vivo studies where melatonin synergistically augmented cytotoxicity and apoptosis in Nimotuzumab-treated glioma cells. Thus, melatonin shows promise as a beneficial addition to Nimotuzumab treatment in glioma patients.

Central nervous system complications in SARS-CoV-2-infected patients.

OBJECTIVE: To investigate the clinical manifestations, treatment and prognosis of COVID-19-associated central nervous system (CNS) complications. METHODS: In this single-centre observation study, we recruited patients with COVID-19-associated CNS complications at the neurology inpatient department of the Eighth Affiliated Hospital, Sun Yat-Sen University (Futian, Shenzhen) from Dec 2022 to Feb 2023. Patients were analysed for demographics, clinical manifestations, cerebrospinal fluid properties, electroencephalographic features, neuroimaging characteristics, and treatment outcome. All patients were followed-up at 1 and 2 months after discharge until Apr 2023. RESULTS: Of the 12 patients with COVID-19-associated CNS complications, the CNS symptoms occur between 0 days and 4 weeks after SARS-CoV-2 infection. The most common CNS symptoms were memory deficits (4/12, 33%), Unresponsiveness (4/12, 33%), mental and behavioural disorders (4/12, 33%). Seven of 12 cases can be categorized as probable SARS-CoV-2 encephalitis, and 5 cases can be described as brainstem encephalitis, acute disseminated encephalomyelitis, optic neuritis, multiple sclerosis or tremor probably associated with SARS-CoV-2 infection. Six patients received antiviral therapy, and 11 patients received glucocorticoid therapy, of which 3 patients received human immunoglobulin synchronously. Nine patients recovered well, two patients had residual neurological dysfunction, and one patient passed away from complications associated with tumor. CONCLUSION: In this observational study, we found that the inflammatory or immune-related complications were relatively common manifestations of COVID-19-associated CNS complications, including different phenotypes of encephalitis and CNS inflammatory demyelinating diseases. Most patients recovered well, but a few patients had significant neurological dysfunctions remaining.

Evaluation of Nocturnal Symptoms in Chinese Parkinson's Disease Patients Based on the PDSS-2 Scale: A Multicenter Cross-Sectional Study.

BACKGROUND: Nocturnal symptoms have a significant effect on the quality of life in Parkinson's disease (PD) patients. OBJECTIVE: This study aimed to investigate the prevalence and associated factors of nocturnal symptoms in Chinese PD patients. METHODS: This multicenter cross-sectional study included 1,500 patients with primary PD from 18 centers in China was carried out between February 2019 and February 2020. Questionnaires including Parkinson's disease sleep scale 2 (PDSS-2), Parkinson's disease questionnaire 8 (PDQ-8), Beck depression inventory (BDI), and generalized anxiety disorder scale 7 (GAD-7) were used to assess nocturnal symptoms, quality of life, depression, and anxiety. RESULTS: Among 1,500 Chinese PD patients, 576 (38.4%) reported nocturnal symptoms. Of them, 59.2% were older than 65 years. The PDQ-8 total score was higher in patients with nocturnal symptoms (p < 0.01). Moderate and severe depression was reported more often in patients with nocturnal symptoms (p < 0.01), and the occurrence and severity of anxiety were higher as well (p < 0.01). Longer disease duration and higher Hoehn-Yahr (HY) stage were independently associated with nocturnal symptoms (p < 0.01). Education level, depression, disease course, HY stage, and nocturnal symptoms were related to the quality of life in Chinese PD patients (p < 0.01). CONCLUSION: Our study found that 38.4% of Chinese PD patients have nocturnal symptoms, even in early and mid-stage PD. Nocturnal symptoms were associated with worse quality of life and higher incidences of depression and anxiety. Nocturnal symptoms should be included in the assessment and care plan, especially in patients with longer disease courses and higher HY stages.

Dl-3-n-butylphthalide activates Nrf2, inhibits ferritinophagy, and protects MES23.5 dopaminergic neurons from ferroptosis.

Ferroptosis, a newly identified iron-dependent form of cell death, has recently been implicated in the pathogenesis of Parkinson's disease (PD). Dl-3-n-butylphthalide (NBP) attenuates behavioral and cognitive deficits in animal models of PD. However, the potential of NBP to prevent dopaminergic neuron death by suppressing ferroptosis has rarely been explored. In this study, we aimed to investigate the effects of NBP on ferroptosis in erastin-induced dopaminergic neurons (MES23.5 cells) and the underlying mechanisms involved in these effects. Our results demonstrated that erastin significantly decreased viability of MES23.5 dopaminergic neurons in a dose-dependent manner, which was reversible by ferroptosis inhibitors. We further verified that NBP protected erastin-treated MES23.5 cells from death by inhibiting ferroptosis. Erastin increased the mitochondrial membrane density, caused lipid peroxidation, and decreased GPX4 expression in MES23.5 cells, which could be reversed by NBP preconditioning. NBP pretreatment suppressed erastin-induced labile iron accumulation and reactive oxygen species generation. Moreover, we demonstrated that erastin significantly reduced FTH expression, and pre-administration with NBP promoted Nrf2 translocation into the nucleus and increased the protein level of FTH. Additionally, the expression of LC3B-II in MES23.5 cells pretreated with NBP before administration of erastin was lower than that in cells treated with erastin alone. NBP reduced colocalization of FTH and autophagosomes in MES23.5 cells exposed to erastin. Finally, erastin gradually inhibited NCOA4 expression in a time-dependent manner, which was reversible by NBP pretreatment. Taken together, these results indicated that NBP suppressed ferroptosis via regulating FTH expression, which was achieved by promoting Nrf2 nuclear translocation and inhibiting NCOA4-mediated ferritinophagy. As such, NBP may be a promising therapeutic agent for the treatment of neurological diseases associated with ferroptosis.

α-Synuclein Induces Neuroinflammation Injury through the IL6ST-AS/STAT3/HIF-1α Axis.

The aggregation of α-synuclein (α-syn) promotes neuroinflammation and neuronal apoptosis, which eventually contribute to the pathogenesis of Parkinson's disease (PD). Our microarray analysis and experimental data indicated a significant expression difference of the long noncoding RNA IL6ST-AS and its anti-sense strand, IL6ST, in α-synuclein-induced microglia, compared with unstimulated microglia. IL6ST is a key component of the IL6R/IL6ST complex in the microglial membrane, which recognizes extracellular inflammatory factors, such as IL6. Studies have shown that the binding of IL6 to the IL6R/IL6ST complex could activate the JAK2-STAT3 pathway and promote an excessive immune response in glia cells. Meanwhile, the phosphorylation and activation of STAT3 could increase the transcription of HIF1A, encoding a hypoxia-inducible factor related to cytotoxic damage. Our results indicated that the overexpression of IL6ST-AS induced by exogenous α-synuclein could inhibit the expression of IL6ST and the activation of JAK2-STAT3 pathway in HMC3 cells. In addition, a reduction in STAT3 resulted in the transcription inhibition of HIF1A and the acceleration of oxidative stress injury in SH-SY5Y cells co-cultured with α-synuclein-induced HMC3 cells. Our findings indicate that IL6ST-AS is an important factor that regulates microglia activation and neuronal necrosis in the progression of PD. In the HMC3 and SH-SY5Y cell co-culture system, the overexpression of IL6ST-AS led to microglial dysfunction and neurotoxicology through the IL6ST-AS/STAT3/HIF-1α axis. Our research revealed the relationships among α-synuclein, IL6ST, STAT3, and HIF-1α in the pathological process of PD and provided a new inflammation hypothesis for the pathogenesis of PD.

The XINDI Study: A Randomized Phase III Clinical Trial Evaluating the Efficacy and Safety of Safinamide as Add-On Therapy to Levodopa in Chinese Patients with Parkinson's Disease with Motor Fluctuations.

BACKGROUND: Levodopa remains the gold standard for the treatment of Parkinson's disease, but its long-term use is associated with motor complications whose management is still a significant challenge. Safinamide is a multimodal drug with proven efficacy as an adjunct to levodopa. OBJECTIVE: The objective of this study was to investigate the efficacy and safety of safinamide as an add-on to levodopa in Chinese patients with Parkinson's disease with motor fluctuations. METHODS: The XINDI study was a phase III, randomized, double-blind, placebo-controlled, multicenter study, with a 2-week screening period and a 16-week treatment period. The starting dose of safinamide (or placebo) was 50 mg once daily, increased to 100 mg once daily at day 15. Patients aged ≥  18 years, with idiopathic Parkinson's disease of >3 years duration, Hoehn and Yahr stage 1-4, and daily OFF time ≥  1.5 h, were eligible. Patients should follow a stable oral levodopa regimen and may receive concomitant treatment with stable doses of other anti-Parkinson drugs, except monoamine oxidase-B inhibitors. Patients with severe disabling peak-dose or biphasic dyskinesia, unpredictable or widely swinging fluctuations, other forms of parkinsonism, a history of dementia or severe cognitive dysfunction, major psychiatric illnesses, and/or clinically significant medical illnesses were excluded. The primary efficacy endpoint was the change from baseline to week 16 in the mean daily OFF time. Secondary efficacy endpoints included the Unified Parkinson's Disease Rating Scale, the Numerical Rating Scale, the Clinical Global Impression scale, and the 39-Item Parkinson's Disease Questionnaire scale. The statistical analysis of the efficacy parameters was conducted using an analysis of co-variance, except for the Clinical Global Impression scale scores that were assessed using the Wilcoxon-Mann-Whitney test. Safety was evaluated through the frequency of adverse events and serious adverse events, physical examination, vital signs, 12-lead electrocardiograms, and laboratory exams. All safety endpoints were summarized using descriptive statistics. RESULTS: The trial enrolled 307 patients. At week 16, the difference in the change of the mean total daily OFF time between safinamide and placebo groups was 1.10 h (p < 0.0001). This change was significantly greater in the safinamide group starting from week 2, suggesting a rapid onset of drug efficacy. ON time, Unified Parkinson's Disease Rating Scale, Clinical Global Impression scale, and the 39-Item Parkinson's Disease Questionnaire showed statistically significant improvements. There were no significant between-group differences for adverse events or serious adverse events. CONCLUSIONS: Safinamide, as add-on therapy to levodopa, significantly reduced motor fluctuations and improved motor symptoms and quality of life of Chinese patients with idiopathic Parkinson's disease. The improvements observed in the Unified Parkinson's Disease Rating Scale total and motor scores were also clinically significant. No safety concerns were identified, confirming the good tolerability profile of the drug. CLINICAL TRIAL REGISTRATION: NCT03881371, registered on 19 March, 2019, https://clinicaltrials.gov/NCT03881371 .

The Value of HPA Axis Hormones as Biomarkers for Screening and Early Diagnosis of Postpartum Depression: Updated Information About Methodology.

Because of the high prevalence of postpartum depression (PPD) and the suffering involved, early diagnosis is urgent; however, current screening tools and diagnosis are inadequate. In addition to conventional methods such as the Edinburgh Postnatal Depression Scale and clinical interviews, several hormones in the hypothalamic-pituitary-adrenal (HPA) axis, such as corticotrophin-releasing hormone, adrenocorticotropic hormone, and cortisol, have been considered because of their critical roles in stress regulation in the mothers. The study designs are complicated, however, and so the effectiveness of these hormones as biomarkers for PPD is still controversial. Such inconsistency may have resulted from the variation in methodology between studies. The methodology problems in the investigation of PPD and HPA axis hormones have not been reported extensively. We therefore sought to summarize the methodological problems of studies published in the past decade, including the strengths and weaknesses of the examinations and the technological difficulties involved. Our findings suggest that (a) suitable samples and appropriate detection methods would reduce heterogeneity among trials; (b) the cutoff value of the scale test should be carefully selected for determining the performance of biomarker tests; (c) evaluation methods and criteria should be chosen with consideration of the tools feasible for use in local hospitals and population; and (d) the cost of diagnosis should be reduced. We hope that these findings provide insight for future investigations of HPA axis hormones as biomarkers for screening and early diagnosis of PPD.

Exploration of the α-syn/T199678/miR-519-3p/KLF9 pathway in a PD-related α-syn pathology.

BACKGROUND: Kruppel-like factor 9 (KLF9) plays a key role as an inducer of cellular oxidative stress in the modulation of cell death and in oxidant-dependent tissue injury. Our previous study indicated that lncRNA-T199678 (T199678) affected the expression of KLF9 in an α-synuclein (α-syn) induced cellular model. However, the roles of interactions among α-syn, T199678, KLF9 and related microRNAs (miRNAs) in the Parkinson's disease (PD)-related α-syn pathology are unclear and were therefore investigated in this study. METHODS: An α-syn-injected mouse model and an α-syn exposed SY-SH5Y cellular model were used in this study. We confirmed the utility of these established models with morphological and behavioral methods. We checked how expression of T199678 and KLF9 were affected by α-syn and demonstrated their interaction by fluorescence in situ hybridization (FISH) staining and western blots. We analyzed expression in ROS+ cells by immunohistochemistry. Finally, we obtained seven miRNAs through bioinformatic analysis simultaneously affected by T199678 and α-syn and verified these with RT-PCR. RESULTS: We found that expression of KLF9 was regulated by T199678, whereas expression of T199678 was not affected by KLF9 in the α-syn exposed SY-SH5Y cells. These findings suggest that KLF9 is the downstream gene regulated by T199678, whereas miR-519-3p may play a contributing role. We also confirmed that α-syn injection upregulated the expression of ROS, which could be downregulated by upregulation of T199678, indicating an anti-oxidative role of T199678 in the α-syn-related mechanisms. CONCLUSIONS: Our results indicate the existence of a potential α-syn/T199678/miR-519-3p /KLF9 pathway in PD-related α-syn pathology. This pathway might explain oxidative stress processes in α-syn-related mechanisms, which requires further verification.

Evaluation of the reliability of the criteria for assessing prescription quality in Chinese hospitals among pharmacists in China.

BACKGROUND: The reliability of Criteria for Assessing Prescription Quality in Chinese Hospitals (CAPQCH) has never been rigorously verified. This study was designed to verify the reliability of the CAPQCH among pharmacists in China. METHODS: Fourteen pharmacists, 5 from hospitals and 9 from the communities were recruited. We randomly selected 200 prescriptions, and made the testing prescriptions including appropriate and inappropriate testing prescriptions. Pharmacists assessed these testing prescriptions according to criteria in CAPQCH. Three test sets (Set 1, Set 2, and Set 3) were evaluated at 6-month intervals. Before administration of Set 3, pharmacists were informed that achievement on Set 3 would be reflected in their performance appraisal. We also evaluated the performance based on prescription comments before and after combining several confusing criteria. Cohen's Kappa statistic, Fleiss' Kappa statistic, and accuracy were employed to evaluate reliability among pharmacists. RESULTS: Median values of Cohen's Kappa were 0.61 in Set 1, 0.66 in Set 2, and 0.80 in Set 3; reliability is thus substantial. Our data indicate no significant differences between Set 1 and Set 2, whereas Set 3 indicates significantly improved performance. Moreover, combinations of confusing criteria contributed little to improvement of performance in prescription comments. CONCLUSION: Our results verified the reliability of CAPQCH application by working pharmacists. Adding performance based on prescription comments to personal appraisals was effective in improving the quality of prescription comments. These findings may be useful when future modification of the CAPQCH is considered. Moreover, this study contributes to improving the understanding of the prescription assessment situation in China.

Exploration of a Brain-Liver-Communication-Related Mechanism Involved in the Experimental Perimenopausal Depression Rat Model using Chaihu-Shugan-San.

Existing research suggests the involvement of a brain-liver-communication-related mechanism in the occurrence of depression. In this study, we selected Chaihu-Shugan-San (CSS), a traditional Chinese herbal medicine that can simultaneously affect liver and depression, as a probe to investigate the involvement of the brain-liver-communication-related mechanism in perimenopausal depression. A total of 50 experimental perimenopausal depression rat models were established by ovariectomy surgery (PMS) followed by chronic unpredictable mild stress (CUMS) processes. Animals underwent CSS treatment or treatments with CSS + Ly294002, an inhibitor of the PI3K/Akt signalling pathway. We observed the behavioural performances of depression and anxiety, serum concentrations of biochemical indices, serum estrogen two levels, hippocampal 5-HT and NE levels and the morphological changes in liver tissues. The protein and mRNA expressions of PI3K and Akt were also evaluated. CSS treatment significantly ameliorated the behavioural performance, partial biochemical indices and the morphological changes in the liver tissues of PMS + CUMS rats. Ly294002 partially inhibited the CSS effects. The expressions of PI3K and Akt were significantly downregulated by PMS + CUMS processes but upregulated by CSS treatment, which could be significantly suppressed by Ly294002. A brain-liver-communication-related mechanism may be involved in perimenopausal depression, where the PI3K/Akt signalling pathway plays a vital role.

Effects of miRNAs in exosomes derived from α-synuclein overexpressing SH-SY5Y cells on autophagy and inflammation of microglia.

Our previous study has revealed that GFP-α-synuclein overexpressing SH-SY5Y cells-derived exosomes (GFP-SNCA Exo) decrease autophagy in microglia via their load of miRNAs. However, it is unclear whether GFP-SNCA Exo can affect microglial inflammation via modulation of autophagy. In order to investigate the effects of miRNAs carried by GFP-SNCA Exo on autophagy and inflammation of microglia. SH-SY5Y cells were transfected with lentivirus expressing α-synuclein and then their exosomes were collected. Western blot and laser confocal images showed that α-synuclein transferred between SH-SY5Y cells and microglia through exosomes. Differentially expressed miRNAs between GFP-SNCA Exo and the vector exosomes were detected by microarray analysis. After bioinformatics analysis of the differentially expressed miRNAs, we found that their target genes were enriched in the MAPK and autophagy-associated signaling pathway. The expression of P62, p-JNK/JNK, and p-ERK/ERK and the release of IL-6 significantly increased whereas LC3 II/I decreased in microglia exposed to GFP-SNCA Exo for 48 h when compared to the control group. But rapamycin could reverse the increasing expression of p-JNK/JNK, p-ERK/ERK and the release of IL-6 induced by GFP-SNCA Exo. Dual immunofluorescence staining for LC3B and LAMP1 showed that the fluorescence density of LC3B decreased and the fluorescence of LC3B and LAMP1 were not co-located in microglia after 48 h co-culture with GFP-SNCA Exo compared with the control group, which indicated that these exosomes decreased autophagy and impaired the autophagy flux in recipient microglia. Taken together, our results indicate that GFP-SNCA Exo activate the MAPK signaling pathway and inflammation by decreasing autophagy in microglia.

Galvanic vestibular stimulation with low intensity improves dynamic balance.

BACKGROUND: Dynamic balance is associated with fall risk. The aim of this study is to explore the effects of galvanic vestibular stimulation with very low intensity direct current (dcGVS) on dynamic balance. METHODOLOGY: We used a rocker force platform for assessing the dynamic balance performance. Center-of-pressure (COP) coordinates were acquired and decomposed to rambling (RA) and trembling (TR). We measured sway parameters, including length, average speed, and average range, affected by dcGVS at 0.01 mA with eyes open (EO) and eyes closed (EC). RESULTS: We assessed 33 young healthy subjects and found that all sway parameters were shorter in the EO condition, indicating a better dynamic balance performance. dcGVS significantly improved the dynamic balance performance both in EO and EC conditions. All the sway parameters in COP in EO were significantly shorter than those in EC, indicating a better dynamic balance performance in EO. In EO, RA had greater improvement rates than TR. In EC, only average speed had a greater improvement rate in RA, whereas length and average range had greater improvement rates in TR. These results indicate a different modulation model between EO and EC. CONCLUSION: These findings indicate that very low intensity dcGVS improved the sway parameters of dynamic balance in young healthy subjects. Moreover, our results suggest different dynamic balance control models between having EO and EC. The mechanisms of these phenomena caused by very low intensity dcGVS require further investigation.

Verification of pain-related neuromodulation mechanisms of icariin in knee osteoarthritis.

Knee osteoarthritis (KOA) is a common disease with no specific treatment. Icariin (ICA) is considered an agent for KOA. This study aimed to confirm the pain-related neuromodulation mechanisms of ICA on KOA. Three experiments were designed: (1) verifying the therapeutic effects of ICA in vivo and in vitro, (2) exploring the potential pain-related neuromodulation pathways involved in ICA treatment by functional magnetic resonance imaging (fMRI) and virus retrograde tracing (VRT) and (3) confirming the pain-related targets by tandem mass tag (TMT)-based quantitative proteomics and bioinformatic analyses. Experiment 1 verified the efficacy of ICA in OA animal and cell models. Experiment 2 found a series of brain regions associated with KOA reversed by ICA treatment, indicating that a pain-related hypothalamic-mediated neuromodulation pathway and an endocannabinoid (EC)-related pathway contribute to ICA mechanisms. Experiment 3 explored and confirmed four pain-related genes involved in KOA and ICA treatment. We confirmed the key role of pain-related neuromodulation mechanisms in ICA treatment associated with its analgesic effect. Our findings contribute to considering ICA as a novel therapy for KOA.

Alpha-Synuclein Accumulation and Its Phosphorylation in the Enteric Nervous System of Patients Without Neurodegeneration: An Explorative Study.

Alpha-synuclein (α-Syn) is widely distributed and involved in the regulation of the nervous system. The phosphorylation of α-Syn at serine 129 (pSer129α-Syn) is known to be closely associated with α-Synucleinopathies, especially Parkinson's disease (PD). The present study aimed to explore the α-Syn accumulation and its phosphorylation in the enteric nervous system (ENS) in patients without neurodegeneration. Patients who underwent colorectal surgery for either malignant or benign tumors that were not suitable for endoscopic resection (n = 19) were recruited to obtain normal intestinal specimens, which were used to assess α-Syn immunoreactivity patterns using α-Syn and pSer129α-Syn antibodies. Furthermore, the sub-location of α-Syn in neurons was identified by α-Syn/neurofilament double staining. Semi-quantitative counting was used to evaluate the expression of α-Syn and pSer129α-Syn in the ENS. Positive staining of α-Syn was detected in all intestinal layers in patients with non-neurodegenerative diseases. There was no significant correlation between the distribution of α-Syn and age (p = 0.554) or tumor stage (p = 0.751). Positive staining for pSer129α-Syn was only observed in the submucosa and myenteric plexus layers. The accumulation of pSer129α-Syn increased with age. In addition, we found that the degenerative changes of the ENS were related to the degree of tumor malignancy (p = 0.022). The deposits of α-Syn were present in the ENS of patients with non-neurodegenerative disorders; particularly the age-dependent expression of pSer129α-Syn in the submucosa and myenteric plexus. The current findings of α-Syn immunostaining in the ENS under near non-pathological conditions weaken the basis of using α-Syn pathology as a suitable hallmark to diagnose α-Synucleinopathies including PD. However, our data provided unique perspectives to study gastrointestinal dysfunction in non-neurodegenerative disorders. These findings provide new evidence to elucidate the neuropathological characteristics and α-Syn pathology pattern of the ENS in non-neurodegenerative conditions.

LncRNA-T199678 Mitigates α-Synuclein-Induced Dopaminergic Neuron Injury via miR-101-3p.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by dopaminergic neuron death and the abnormal accumulation and aggregation of α-synuclein (α-Syn) in the substantia nigra (SN). Although the abnormal accumulation of α-Syn can solely promote and accelerate the progress of PD, the underlying molecular mechanisms remain unknown. Mounting evidence confirms that the abnormal expression of long non-coding RNA (lncRNA) plays an important role in PD. Our previous study found that exogenous α-Syn induced the downregulation of lncRNA-T199678 in SH-SY5Y cells via a gene microarray analysis. This finding suggested that lncRNA-T199678 might have a potential pathological role in the pathogenesis of PD. This study aimed to explore the influence of lncRNA-T199678 on α-Syn-induced dopaminergic neuron injury. Overexpression of lncRNA-T199678 ameliorated the neuron injury induced by α-Syn via regulating oxidative stress, cell cycle, and apoptosis. Studies indicate lncRNAs could regulate posttranscriptional gene expression via regulating the downstream microRNA (miRNA). To discover the downstream molecular target of lncRNA-T199678, the following experiment found out that miR-101-3p was a potential target for lncRNA-T199678. Further study showed that the upregulation of lncRNA-T199678 reduced α-Syn-induced neuronal damage through miR-101-3p in SH-SY5Y cells and lncRNA-T199678 was responsible for the α-Syn-induced intracellular oxidative stress, dysfunction of the cell cycle, and apoptosis. All in all, lncRNA-T199678 mitigated the α-Syn-induced dopaminergic neuron injury via targeting miR-101-3p, which contributed to promote PD. Our results highlighted the role of lncRNA-T199678 in mitigating dopaminergic neuron injury in PD and revealed a new molecular target for PD.

Rifampicin attenuates rotenone-treated microglia inflammation via improving lysosomal function.

Mounting evidence suggests that lysosome dysfunction promotes the progression of several neurodegenerative diseases via hampering autophagy flux. While regulation of autophagy in microglia may affect chronic inflammation involved in Parkinson's disease (PD). Our previous studies have reported rifampicin inhibits rotenone-induced microglia inflammation by enhancing autophagy, however the precise mechanism remains unclear. Human microglia (HM) cells were pretreated with 100 µM rifampicin for 2 h followed by exposure to 0.1 µM rotenone. We found that rifampicin pretreatment suppressed the gene expression of IL-1ß and IL-6 via inhibiting activation of JNK after rotenone induction, but the anti-inflammatory effect of rifampicin was reversed by chloroquine. Moreover, rifampicin pretreatment not only improved the ratio of LC3-II/LC3-I in rotenone-treated cells, but also increased autolysosomes and decreased autophagosomes in RFP-GFP-LC3B transfected HM cells exposed to rotenone, thus indicating rifampicin improves autophagy flux in rotenone-treated HM cells. Finally, we verified rifampicin pretreatment enhanced ATP6V0A1 expression when compared to that exposed to rotenone alone. ATP6V0A1 knockdown inhibited the effect of rifampicin on maintaining lysosome acidification and autophagosome-lysosome fusion in rotenone-treated microglia. Taken together, our results indicated that rifampicin attenuates rotenone-induced microglia inflammation partially via elevating ATP6V0A1. Modulation of lysosomal function by rifampicin may be a novel therapeutic strategy for PD.

α-synuclein accumulation in SH-SY5Y cell impairs autophagy in microglia by exosomes overloading miR-19a-3p.

Aims: To reveal whether miRNAs in exosomes from α-synuclein transgenic SH-SY5Y cells are able to regulate autophagy in recipient microglia. Materials & methods: Microarray analysis and experimental verification were adopted to assess the significance of autophagy-associated miRNAs in exosomes from neuronal model of α-synucleinopathies. Results: We found that miR-19a-3p increased remarkably in the exosomes from α-synuclein gene transgenic SH-SY5Y cells. Further study inferred that α-synuclein gene transgenic SH-SY5Y cell-derived exosomes and miR-19a-3p mimic consistently inhibited the expression of phosphatase and tensin homolog and increased the phosphorylation of AKT and mTOR, both of which ultimately lead to the dysfunction of autophagy in recipient microglia. Conclusion: The data suggested that enhanced expression of miR-19a-3p in exosomes suppress autophagy in recipient microglia by targeting the phosphatase and tensin homolog/AKT/mTOR signaling pathway.

Curcumin-loaded PLGA-PEG nanoparticles conjugated with B6 peptide for potential use in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder mainly characterized by ß-amyloid deposit and tau hyperphosphorylation with no curative treatments. Curcumin (Cur) has been proved to have potential use in Alzheimer's disease with its anti-amyloid, anti-inflammatory, and anti-oxidant properties, etc. However, its hydrophobicity and low bioavailability hinder its application. In this paper, we designed a novel brain-target nanoparticle, poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG) conjugated with B6 peptide and was loaded with Cur (PLGA-PEG-B6/Cur) and administered it into HT22 cells and APP/PS1 Al transgenic mice. The in vitro assays including dynamic light scattering (DLS), flow cytometry (FCM), red blood cell (RBC) lysis, and thromboelastography (TEG) analysis indicated that this nanoparticle could narrow the diameter of Cur, increase its cellular uptake and possess good blood compatibility. The results from Morris water maze proved that PLGA-PEG-B6/Cur could tremendously improve the spatial learning and memory capability of APP/PS1 mice, compared with native Cur. The ex vivo assays including Bielschowsky silver staining, immunostaining, and western blotting demonstrated that PLGA-PEG-B6/Cur could reduce hippocampal ß-amyloid formation and deposit and tau hyperphosphorylation. Thus, we suggested that PLGA-PEG-B6/Cur nanoparticles would be of potential and promising use for the treatment of Alzheimer's disease.

Chronic back pain cured by low-dose levodopa: is it a variant of restless legs syndrome?

Chronic back pain is one of the most common reasons for missed work and visits to the doctor. This report presents 2 interesting cases of chronic back pain that were effectively relieved by low-dose levodopa. These 2 patients showed no sign of anatomical problem of the spine or relative structures, but the discomforts on the back manifested some characteristics resembling those in restless legs syndrome (RLS), and one of them actually developed RLS after many years of back problem. We believe that this type of chronic back pain might be a variant of RLS, which we would like to call "restless back", and it can be effectively treated by dopaminergic drugs.