A metabolome atlas of mouse brain on the global metabolic signature dynamics following short-term fasting.

Calorie restriction (CR) or a fasting regimen is considered one of the most potent non-pharmacological interventions to prevent chronic metabolic disorders, ameliorate autoimmune diseases, and attenuate aging. Despite efforts, the mechanisms by which CR improves health, particularly brain health, are still not fully understood. Metabolic homeostasis is vital for brain function, and a detailed metabolome atlas of the brain is essential for understanding the networks connecting different brain regions. Herein, we applied gas chromatography-mass spectrometry-based metabolomics and lipidomics, covering 797 structurally annotated metabolites, to investigate the metabolome of seven brain regions in fasted (3, 6, 12, and 24 h) and ad libitum fed mice. Using multivariate and univariate statistical techniques, we generated a metabolome atlas of mouse brain on the global metabolic signature dynamics across multiple brain regions following short-term fasting (STF). Significant metabolic differences across brain regions along with STF-triggered region-dependent metabolic remodeling were identified. We found that STF elicited triacylglycerol degradation and lipolysis to compensate for energy demand under fasting conditions. Besides, changes in amino acid profiles were observed, which may play crucial roles in the regulation of energy metabolism, neurotransmitter signaling, and anti-inflammatory and antioxidant in response to STF. Additionally, this study reported, for the first time, that STF triggers a significant elevation of N-acylethanolamines, a class of neuroprotective lipids, in the brain and liver. These findings provide novel insights into the molecular basis and mechanisms of CR and offer a comprehensive resource for further investigation.

Nanotherapeutic and Stem Cell Therapeutic Strategies in Neurodegenerative Diseases: A Promising Therapeutic Approach.

Neurodegeneration is characterized by progressive, disabling, and incurable neurological disorders with the massive loss of specific neurons. As one of the most promising potential therapeutic strategies for neurodegenerative diseases, stem cell therapy exerts beneficial effects through different mechanisms, such as direct replacement of damaged or lost cells, secretion of neurotrophic and growth factors, decreased neuroinflammation, and activation of endogenous stem cells. However, poor survival and differentiation rates of transplanted stem cells, insufficient homing ability, and difficulty tracking after transplantation limit their further clinical use. The rapid development of nanotechnology provides many promising nanomaterials for biomedical applications, which already have many applications in neurodegenerative disease treatment and seem to be able to compensate for some of the deficiencies in stem cell therapy, such as transport of stem cells/genes/drugs, regulating stem cell differentiation, and real-time tracking in stem cell therapy. Therefore, nanotherapeutic strategies combined with stem cell therapy is a promising therapeutic approach to treating neurodegenerative diseases. The present review systematically summarizes recent advances in stem cell therapeutics and nanotherapeutic strategies and highlights how they can be combined to improve therapeutic efficacy for the treatment of neurodegenerative diseases.

Intrastriatal injection of Parkinson's disease intestine and vagus lysates initiates α-synucleinopathy in rat brain.

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain and the pathological accumulation of misfolded α-synuclein (α-syn) in the brain. A growing body of evidence suggests that the formation of misfolded α-syn and aggregation may begin in the peripheral nervous system, specifically the enteric nervous system, and then propagate to the central nervous system via the vagus nerve. However, the PD-like neuropathology induced by the intestine and vagus nerve extracts is rarely investigated. In this work, we injected lysates of the intestine and vagus obtained from a diagnosed PD patient, which contained abnormal α-syn aggregates, into the rat striatum unilaterally. Strikingly, such an injection induced dopaminergic neurodegeneration and α-syn depositions in the striatum, substantia nigra, and other brain regions, including the frontal cortex, somatosensory cortex, hypothalamus, brain stem, and cerebellum. Moreover, significant activation of microglia and the development of astrogliosis were observed in the substantia nigra pars compacta of the injected rats. These findings provide essential information for our understanding of PD pathogenesis, as we established for the first time that the α-syn aggregates in the intestine and vagus of a PD patient were sufficient to induce prion-like propagation of endogenous α-syn pathology in wild-type rats.

PM2.5 exposure triggers cell death through lysosomal membrane permeabilization and leads to ferroptosis insensitivity via the autophagy dysfunction/p62-KEAP1-NRF2 activation in neuronal cells.

PM2.5 exposure can be associated with the onset of neurodegenerative diseases, with oxidative stress-induced cellular homeostasis disruption and cell death as one of the main mechanisms. However, the exact cellular and molecular processes are still rarely investigated. Autophagy and KEAP1-NRF2 (Kelch-like ECH-Associating protein 1-nuclear factor erythroid 2 related factor 2) signaling pathway are two main cellular defense systems for maintaining cellular homeostasis and resisting oxidative stress. In this study, we primarily investigated the role of autophagy and KEAP1-NRF2 in regulating cell death resulting from PM2.5 exposure in mouse neuroblastoma N2a cells. Our results showed that PM2.5 exposure disrupted autophagic flux by impairing lysosomal function, including lysosomal alkalinization, increased lysosome membrane permeabilization (LMP), and Cathepsin B release. Furthermore, dysregulated autophagy enhances NRF2 activity in a p62-dependent manner, which then initiates the expression of a series of antioxidant genes and increases cellular insensitivity to ferroptosis. Meanwhile, autophagy dysfunction impairs the intracellular degradation of ferroptosis related proteins such as GPX4 and ferritin. As these proteins accumulate, cells also become less sensitive to ferroptosis. LMP-associated cell death may be the main mechanism of PM2.5-induced N2a cytotoxicity. Our results may provide insights into the mechanisms of PM2.5-induced neurotoxicity and predict effective prevention and treatment strategies.

Pitx3 deficiency promotes age-dependent alterations in striatal medium spiny neurons.

Background: The classical motor symptoms of Parkinson's disease (PD) are tightly linked to the gradual loss of dopamine within the striatum. Concomitantly, medium spiny neurons (MSNs) also experience morphological changes, such as reduced dendritic complexity and spine density, which may be potentially associated with motor dysfunction as well. Thus, MSNs may serve as the emerging targets for PD therapy besides the midbrain dopaminergic neurons. Results: To comprehensively examine pathological alterations of MSNs longitudinally, we established a TH Cre/ Pitx3 fl/fl (Pitx3cKO ) mouse model that developed canonical PD features, including a significant loss of SNc DAergic neurons and motor deficits. During aging, the targeted neurotransmitter, MSNs morphology and DNA methylation profile were significantly altered upon Pitx3 deficiency. Specifically, dopamine, GABA and glutamate decreased in the model at the early stage. While nuclear, soma and dendritic atrophy, as well as nuclear invaginations increased in the aged MSNs of Pitx3cko mice. Furthermore, more nuclear DNA damages were characterized in MSNs during aging, and Pitx3 deficiency aggravated this phenomenon, together with alterations of DNA methylation profiling associated with lipoprotein and nucleus pathway at the late stage. Conclusion: The early perturbations of the neurotransmitters within MSNs may potentially contribute to the alterations of metabolism, morphology and epigenetics within the striatum at the late stage, which may provide new perspectives on the diagnosis and pathogenesis of PD.

Risk of ischemic stroke in patients with COVID-19 infection: A systematic review and meta-analysis.

An ongoing global pandemic, the coronavirus disease 2019 is posing threat to people all over the world. The association between COVID-19 and the risk of ischemic stroke remains unclear. This study systematically reviewed published studies and conducted meta-analysis to evaluate the association between the risk of ischemic stroke and COVID-19. This study was conducted according to guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The protocol used in this study had been registered in the International Prospective Register of Systematic Reviews. EMBASE, PubMed, Cochrane Library and Web of Science were searched from 1st December 2019-19th February 2021. This systematic review and meta-analysis analysed the combined effect estimations based on odds ratios (OR) with the random-effects model. Four studies were screened from 31,634 participants including 171 COVID-19 positive patients with ischemic stroke were included. The mean age of COVID-19 positive patients with ischemic stroke was 69.45 years (Range: 63-77 years) and the male patients were 56%. Countries covered by these articles were USA, Italy and France. Three of the articles were retrospective cohort studies and one was prospective cohort study. Our analysis revealed that the risk of ischemic stroke (combined OR: 2.41; 95% CI: 1.08-5.38) was significantly increased. Four included studies were significantly heterogeneous (I2 = 75.2%, P = 0.007). Significant association between the risk of ischemic stroke and COVID-19 was observed in the North America group (combined OR: 2.90; 95% CI: 0.45-18.80, I2 = 89.60%, P = 0.002). This study found that the risk for ischemic stroke was increased in COVID-19 patients, especially in patients from North America. Further studies with larger sample sizes that include different ethnic populations are required to confirm our analysis.

The significance of sialylation on the pathogenesis of Alzheimer's disease.

Sialylation, one of the most common and complex modes of glycosylation, corresponds with the development of the infant brain and nervous system. The most prevalent neurodegenerative disease is Alzheimer's disease (AD), which is mainly characterized by cognitive decline and behavioral disorders. However, the relationship between sialylation and AD occurrence is poorly understood. In this article, we reviewed the role of sialylation on the occurrence and development of AD, then discussed the value of sialylation modification for AD diagnosis and treatment.

Tetrahedral DNA nanostructures functionalized by multivalent microRNA132 antisense oligonucleotides promote the differentiation of mouse embryonic stem cells into dopaminergic neurons.

MicroRNA132 (miR132) negatively regulates the differentiation of mouse embryonic stem cells (ESCs) into dopaminergic (DAergic) neurons; in contrast, antisense oligonucleotide against miR132 (miR132-ASO) effectively blocks the activity of endogenous miR132 and thereafter promotes the differentiation of DAergic neurons. However, it is difficult for miR132-ASO to enter cells without a suitable delivery system. Tetrahedral DNA nanostructures (TDNs), as a new type of DNA-based nanocarrier, have great potential in biomedical applications and even have been reported to promote stem cell differentiation. In this study, we developed functional multivalent DNA nanostructures by appending miR132-ASO motifs to three-dimensional TDNs (miR132-ASO-TDNs). Our data clearly revealed that miR132-ASO-TDNs exposure can promote the differentiation of ESCs into DAergic neurons as well as elevate DA release from differentiated DAergic neurons. MiR132-ASO-TDNs could serve as a novel biofunctional nanomaterial to improve the efficiency of DAergic neurons differentiation. Our findings may also provide a new approach for stem cell therapy against neurodegenerative diseases.

Activation of dopamine receptor D1 inhibits glioblastoma tumorigenicity by regulating autophagic activity.

PURPOSE: Recent studies have reported important roles of dopamine receptors in the early development and progression of glioblastoma (GBM). Here, we tested the antitumor activity of a Dopamine receptor D1 (DRD1) agonist, either alone or in combination with temozolomide (TMZ) on GBM cells. METHODS: Immunofluorescence, immunohistochemistry and Western blotting were used to detect dopamine receptor expression in primary human GBM tissues. In addition, clinical data of GBM patients downloaded from The Cancer Genome Atlas (TCGA) were analyzed. Image-based tracking analysis of LC3 using a mCherry-eGFP-LC3 plasmid was utilized to monitor autophagic flux. Transmission electron microscopy (TEM) was used to visualize aggregation of autophagosomes/autolysosomes. Finally, DRD1 agonist (SKF83959)-induced inhibition of GBM growth was assessed in vitro and in vivo. RESULTS: Positive DRD1 expression was observed in human GBM tissues and found to be related with a good clinical outcome. DRD1 activation specifically inhibited GBM cell growth and significantly disrupted autophagic flux, which led to tumor cell death. Moreover, we found that DRD1 agonist treatment inhibited auto-lysosomal degradation in GBM cells and that this process was calcium overload dependent and related to inhibition of mammalian target of rapamycin (mTOR). Finally, we found that DRD1 agonist and TMZ co-treatment yielded a synergistic therapeutic effect both in vivo and in vitro. CONCLUSIONS: From our data we conclude that DRD1 activation inhibits GBM cell growth and may serve as an alternative avenue for the design of future GBM therapies.

α-Synuclein Negatively Regulates Nurr1 Expression Through NF-κB-Related Mechanism.

The nuclear receptor-related 1 protein (Nurr1) is critical for the development and survival of midbrain dopamine neurons that are predominantly affected and progressively degenerated in Parkinson's disease (PD). The expression level of Nurr1 has been proposed to be modulated by α-synuclein (α-SYN), an important pathological hallmark of PD. However, the underlying molecular mechanisms of α-SYN-Nurr1 interaction are still rarely explored. In this study, we investigated the effect and mechanism of α-SYN on the transcription level of Nurr1. Our results showed that overexpression of α-SYN (WT or A53T) reduced Nurr1 and its downstream gene expressions. α-SYN neither affected the mRNA stability nor bound with the promoter of Nurr1, but modulated the transcription activity of Nurr1 promoter region ranging from -605 bp to -418 bp, which contains the binding site of nuclear factor-kappa B (NF-κB). Moreover, overexpression of α-SYN (WT or A53T) down-regulated NF-κB expression level, thereby inhibiting the transcription factor activity of NF-κB and decreasing the binding quantity of NF-κB with Nurr1 promoter. These findings may give us new insights to better understand the molecular mechanisms underlying the α-SYN-regulated Nurr1 function, which may fascinate the investigation of dopamine neuron degeneration in PD pathogenesis.

Piperine regulates glycogen synthase kinase-3ß-related signaling and attenuates cognitive decline in D-galactose-induced aging mouse model.

Aging-related cholinergic dysfunction, extensive neuroinflammation and oxidative stress in brain are predominant pathogenic factors for dementia. In the present study, we aimed to evaluate the protective effects of piperine, an alkaloid nutrient component of Piper nigrum, against cognitive impairment in a senescent mouse model induced by D-galactose (D-Gal) and to explore the underlying mechanisms. Senescent mouse model was established by repeated subcutaneous injection of D-Gal (150 mg/kg, once daily for 42 days). Fourteen days after the first D-Gal exposure, piperine (2.5, 5, 10 mg/kg) or vehicle was intraperitoneally administered once daily for 28 days. The cognitive function of mice was evaluated by Morris water maze test (MWM). Twenty-four hours after behavioral test, the cholinergic function and oxidative stress level in mouse hippocampus were measured by spectrophotometric assays. In addition, the hippocampal levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß and interleukin-6, were quantified using enzyme-linked immunosorbent assay. Expressions of glycogen synthase kinase-3ß (GSK-3ß) and its upstream or downstream molecules including phosphatidylinositol 3-kinase (PI3K)，protein kinase B (AKT), protein kinase C (PKC), NF-E2-related factor 2, nuclear factor-κB and microtubule-associated protein tau in hippocampus were determined by western blotting, immunohistochemical or immunofluorescent staining. Our data revealed that chronic D-Gal exposure in mice led to cognitive impairment in MWM, along with cholinergic malfunction, extensive oxidative stress and neuroinflammation, as well as hyperphosphorylation of tau protein in hippocampus. All these neurochemical, neuroinflammatory and cognitive alterations could be ameliorated by 4-week repeated piperine administration. Moreover, piperine also reversed D-Gal-induced GSK-3ß activation through modulating PKC and PI3K/AKT pathways in senescent mouse hippocampus, suggesting GSK-3ß-related signaling might be involved in the benefits of piperine against D-Gal-induced cognitive decline in mice.

Piperine attenuates cognitive impairment in an experimental mouse model of sporadic Alzheimer's disease.

Piperine, the major alkaloid constituent of black pepper, has been reported to possess a wide range of pharmacological effects on the central nervous system, including antidepressant, anticonvulsant and anti-ischemic activities. In the present study, we aimed to investigate the therapeutic potential and neuroprotective mechanisms of piperine in an experimental mouse model of sporadic Alzheimer's disease (sAD) induced by intracerebroventricular (ICV) infusion of streptozotocin (STZ). STZ was infused bilaterally at a dose of 1.5 mg/kg/day on day 1 and day 3. From day 8, piperine (2.5-10 mg/kg body weight) was administered intraperitoneally once daily for 15 consecutive days. The locomotor activity and cognitive performance of mice were evaluated using open field test and Morris water maze test, respectively. On day 23, all animals were sacrificed, and the hippocampus was used for biochemical, neurochemical and neuroinflammatory determinations. Our data revealed that the ICV-STZ-infused sAD mouse showed an increased oxidative-nitrosative stress, an altered neurotransmission and an elevated neuroinflammation in hippocampus, as well as significant cognitive deficits. All these alterations can be ameliorated by piperine in a dose-dependent manner. In summary, our findings predict a therapeutic potential of piperine against cognitive deficits in sAD mouse. This effect might be due to its abilities to ameliorate oxidative-nitrosative stress, restore neurotransmission and reduce neuroinflammation.

Elevated Plasma microRNA-105-5p Level in Patients With Idiopathic Parkinson's Disease: A Potential Disease Biomarker.

Parkinson's disease (PD) is the second most common neurodegenerative disease, which still lacks a biomarker to aid in diagnosis and to differentiate diagnosis at the early stage of the disease. microRNAs (miRNAs) are small and evolutionary conserved non-coding RNAs that are involved in post-transcriptional gene regulation. Several miRNAs have been proposed as potential biomarkers in several diseases. In the present study, we screened miRNAs using a network vulnerability analysis, to evaluate their potential as PD biomarkers. We first extracted miRNAs that were differentially expressed between PD and healthy controls (HC) samples. Then we constructed the PD-specific miRNA-mRNA network and screened miRNA biomarkers using a new bioinformatics model. With this model, we identified miR-105-5p as a putative biomarker for PD. Moreover, we measured miR-105-5p levels in the plasma of patients with idiopathic PD (IPD) (n = 319), neurological disease controls (NDC, n = 305) and HC (n = 273) using reverse transcription real-time quantitative PCR (RT-qPCR). Our data clearly demonstrated that the plasma miR-105-5p level in IPD patients was significantly higher than those of HC (251%, p < 0.001) and NDC (347%, p < 0.001). There was no significant difference in miR-105-5p expression between IPD patients with or without anti-PD medications. Interestingly, we found that the plasma miR-105-5p expression level may be able to differentiate IPD from parkinsonian syndrome, essential tremor and other neurodegenerative diseases. We believe that a change in the plasma miR-105-5p level is a potential biomarker for IPD.

Altered Expression Levels of MicroRNA-132 and Nurr1 in Peripheral Blood of Parkinson's Disease: Potential Disease Biomarkers.

MicroRNAs (miRNAs) are small and evolutionary conserved noncoding RNAs that are involved in post-transcriptional gene regulation. Differential expression levels of miRNAs can be used as potential biomarkers of disease. Previous animal studies have indicated that the expression level of miR-132 is negatively correlated with its downstream molecule nuclear receptor related 1 protein (Nurr1), which is one of the key factors for the maintenance of dopaminergic function and is particularly vulnerable in Parkinson's disease (PD). However, this correlation has not been confirmed in human patients with PD. Moreover, the possible involvement of miR-132 during the pathogenesis and progression of PD is not fully investigated. Therefore, in the present study, we determined the peripheral circulation levels of miR-132 and Nurr1 in patients with PD, neurological disease controls (NDC) and healthy controls (HC) by reverse transcription real-time quantitative PCR (RT-qPCR). Our data clearly demonstrated that the plasma miR-132 level in PD was significantly higher than those in HC (178%, p < 0.05) and NDC (188%, p < 0.001). When adjusted for gender and age, higher level of miR-132 expression was associated with the significantly increased risk for PD in males and was closely related with the disease stages and disease severity. Furthermore, peripheral Nurr1 was significantly decreased in PD compared with HC (56%, p < 0.001) and NDC (58%, p < 0.001). Much more interestingly, further analysis revealed a negative correlation between the decreased Nurr1 level and the elevated miR-132 level in PD. All these findings indicated that the combination of a high miR-132 level with the low level of its downstream Nurr1 might be a potential biomarker aiding in the diagnosis of PD and monitoring disease progression.

Concentration Levels, Biological Enrichment Capacities and Potential Health Risk Assessment of Trace Elements in Eichhornia crassipes from Honghu Lake, China.

This study investigated the concentrations of Zn, Cu, Cr, Pb, As and Cd in different tissues of E. crassipes from Honghu Lake. The total concentrations of trace elements in E. crassipes were observed in descending order: Zn (111.6162) > Cu (15.7494) > Cr (7.0466) > Pb (5.6251) > As (3.6831) > Cd (0.1941) mg/kg. The order of the bioconcentration factor (BCF) measured in E. crassipes was Zn > As > Cr > Cu > Pb > Cd > 1, indicating that E. crassipes possessed a strong biological enrichment ability to accumulate a variety of trace elements. The translocation factor (TF) values decreased in the order of Cu > Zn > Cr > As > Pb > Cd, all of which were lower than 1, which showed that the absorption of the trace elements by E. crassipes was mainly accomplished in the roots. Moreover, the health risk assessments showed that the carcinogenic and noncarcinogenic risks of the edible parts of E. crassipes were 26.1 and 4.6 times higher than the maximum acceptable value recommended by the USEPA for adults and children of approximately 39.2- and 6.9-fold, respectively. Children were more sensitive than adults. The main trace elements that led to noncarcinogenic risks were As, Cr and Cu, while Cr and As led to carcinogenic risks. The results of the Pearson correlation showed positive correlations with the concentrations of Zn, Cr and As between E. crassipes and the water as well as negative correlations of the contents of all six trace elements between E. crassipes and the sediment.

Alterations of NURR1 and Cytokines in the Peripheral Blood Mononuclear Cells: Combined Biomarkers for Parkinson's Disease.

Nuclear receptor related 1 protein (NURR1), a transcription factor as key player for maintaining dopamine neuron functions and regulating neuroinflammation in the central nerves system, is a potential susceptibility gene for Parkinson's disease (PD). To ascertain whether the expression levels of NURR1 gene and inflammatory cytokines are altered in patients with PD, we measured their mRNA levels in the peripheral blood mononuclear cells (PBMCs) in 312 PD patients, 318 healthy controls (HC), and 332 non-PD neurological disease controls (NDCs) by quantitative real-time PCR. Our data showed that NURR1 gene expression was significantly decreased in the PBMCs of PD as compared with that of HC and NDC (p < 0.01). Since NURR1 was reported to have regulating effects on neuroinflammation, we assessed the expression levels of cytokines (TNF-α, IL-1ß, IL-4, IL-6, and IL-10) in the PBMCs of PD and controls (HC and NDC). Our results showed that the expression levels of those cytokines were significantly higher than those of controls. Statistical analysis revealed that NURR1 expression presented a negative correlation with the expression of TNF-α, IL-1ß, IL-6, and IL-10, and collectively the measurements of NURR1 plus those cytokines significantly improve the diagnostic accuracy. All these findings suggested that NURR1 is likely to be involved in the process of PD by mediating the neuroinflammation, and the combination of NURR1 and cytokines assessment in the PBMCs can be potential biomarkers for PD diagnosis.

Potential biomarkers of Parkinson's disease revealed by plasma metabolic profiling.

The plasma of Parkinson's disease (PD) patients may contain various altered metabolites associated with the risk or progression of the disease. Characterization of the abnormal metabolic pattern in PD plasma is therefore critical for the search for potential PD biomarkers. We collected blood plasma samples from PD patients and used an LC-MS based metabolomics approach to identify 17 metabolites with significantly altered levels. Metabolic network analysis was performed to place the metabolites linked to different pathways. The metabolic pathways involved were associated with tyrosine biosynthesis, glycerol phospholipid metabolism, carnitine metabolism and bile acid biosynthesis, within which carnitine and bile acid metabolites as potential biomarkers are first time reported. These abnormal metabolic changes in the plasma of patients with PD were mainly related to lipid metabolism and mitochondrial function.

Heavy metals and metalloid distribution in different organs and health risk assessment for edible tissues of fish captured from Honghu Lake.

Honghu Lake is the seventh largest freshwater lake in China, and fishery is one of the most important economic sources for local inhabitants. Toxic metal concentrations in muscle of all analyzed fish species captured from Honghu Lake were generally below China standards, except Cr in crucian carp. The average concentrations were decreased in the following order, Zn (14.65 mg/kg) > Cr (1.25 mg/kg) > Cu (0.5994 mg/kg) > Pb (0.0884 mg/kg) > Cd (0.0069 mg/kg) > As (0.0007 mg/kg). There was no significant health risk in consuming fish captured from Honghu Lake, based on the analysis results of target hazard quotient (THQ), carcinogenic risk (CR), and estimated weekly intake (EWI). Mixed edible fish tissues consuming brought higher carcinogenic risks than muscle consuming. Pb was regarded as the major contributor of potential non-carcinogenic risk, while As of the potential carcinogenic risk. THQ set the most stringent allowed values of the average consuming amount of fish muscle at 1,316 g/d, while CR set the value of mixed fish tissues at 525 g/d.

Tiny But Mighty: Promising Roles of MicroRNAs in the Diagnosis and Treatment of Parkinson's Disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer's disease. To date, the clinical diagnosis of PD is primarily based on the late onset of motor impairments. Unfortunately, at this stage, most of the dopaminergic neurons may have already been lost, leading to the limited clinical benefits of current therapeutics. Therefore, early identification of PD, especially at the prodromal stage, is still a main challenge in the diagnosis and management of this disease. Recently, microRNAs (miRNAs) in cerebrospinal fluid or peripheral blood have been proposed as putative biomarkers to assist in PD diagnosis and therapy. In this review, we systematically summarize the changes of miRNA expression profiles in PD patients, and highlight their putative roles in the diagnosis and treatment of this devastating disease.

CpG demethylation in the neurotoxicity of 1-methyl-4-phenylpyridinium might mediate transcriptional up-regulation of α-synuclein in SH-SY5Y cells.

The accumulation of α-synuclein is the primary pathological hallmark of Parkinson's disease (PD). In PD patients, CpG demethylation of intron-1 has been reported to be associated with α-synuclein up-regulation. Environmental factor, for example neurotoxin, is a major etiological risk factor in PD pathogenesis. However, the role of CpG methylation in neurotoxin-induced PD has not been addressed completely yet. To explore CpG methylation associating with α-synuclein transcription and its underlying mechanisms in the neurotoxin-induced PD pathology, human neuroblastoma SH-SY5Y cells were treated with neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+). Results showed that MPP+ induced demethylation of the whole length of the CpG island around SNCA promoter, and both 6-OHDA and MPP+ resulted in up-regulation of SNCA transcription. The CpG demethylation around promoter resulted in up-regulation of SNCA transcriptional activity. In addition, 6-OHDA and MPP+ induced the reduced levels of DNA methyltransferase (DNMT) 3a and DNMT3b but not DNMT1. These data suggested that CpG demethylation was induced by MPP+ and might mediate up-regulation of SNCA transcription in neurotoxin-induced PD. And down-regulation of both DNMT3a and DNMT3b, but not DNMT1, might contribute to CpG demethylation of the SNCA promoter.