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Citalopram and escitalopram are structurally close-related antidepressants and both forms are widely used in the world. We aimed to comparatively evaluate the anti-neuroinflammatory and neuroprotective effects of escitalopram and citalopram in Parkinson's disease (PD) mouse model. Mice were randomly divided into six groups and received 6-hydroxydopamine (6-OHDA) or vehicle administration. The mice were then treated with escitalopram, citalopram or saline for consecutive 7 days. Behaviors, neuroinflammation, neurotransmitters, and neurotoxicity were assessed. Results showed that citalopram but not escitalopram worsened body weight loss and increased freezing time in the PD mice. Both drugs had no impact on the anxiety-like behaviors but ameliorated the depressive-like behaviors as in elevated plus maze and sucrose splash tests. Escitalopram but not citalopram ameliorated motor discoordination in the PD mice as in rotarod test. In accordance, escitalopram but not citalopram attenuated the 6-OHDA-induced nigrostriatal dopaminergic loss. Further mechanistic investigations showed that both drugs mitigated activations of microglia and astrocytes and/or levels of pro-inflammatory cytokines in the PD mice, but escitalopram showed appreciably better effects in the substantia nigra. Neurotransmitter examination in the prefrontal cortex suggested that the two drugs had comparable effects on the disturbed neurotransmitters in the PD mice, but citalopram was prone to disrupt certain normal homeostasis. In conclusion, escitalopram is moderately superior than citalopram to suppress neuroinflammation and to protect against dopaminergic neuronal death and motor discoordination in the 6-OHDA-induced PD mice. Our findings imply that escitalopram shall be prescribed with priority over citalopram to treat PD patients with depression as escitalopram may meanwhile provide greater additional benefits to the patients.
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Citalopram , Modelos Animales de Enfermedad , Escitalopram , Fármacos Neuroprotectores , Oxidopamina , Animales , Citalopram/farmacología , Citalopram/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Masculino , Ratones , Escitalopram/uso terapéutico , Escitalopram/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/inmunología , Ratones Endogámicos C57BL , Citocinas/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Humanos , Conducta Animal/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/inducido químicamenteRESUMEN
BACKGROUND: Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD). The apolipoprotein E (APOE) ε4 genotype increases the risk of Alzheimer's disease (AD). However, the effect of APOEε4 on cognitive function of PD patients remains unclear. In this study, we aimed to understand whether and how carrying APOEε4 affects cognitive performance in patients with early-stage and advanced PD. METHODS: A total of 119 Chinese early-stage PD patients were recruited. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Hamilton anxiety scale, Hamilton depression scale, non-motor symptoms scale, Mini-mental State Examination, Montreal Cognitive Assessment, and Fazekas scale were evaluated. APOE genotypes were determined by polymerase chain reactions and direct sequencing. Demographic and clinical information of 521 early-stage and 262 advanced PD patients were obtained from Parkinson's Progression Marker Initiative (PPMI). RESULTS: No significant difference in cognitive performance was found between ApoEε4 carriers and non-carriers in early-stage PD patients from our cohort and PPMI. The cerebrospinal fluid (CSF) Amyloid Beta 42 (Aß42) level was significantly lower in ApoEε4 carrier than non-carriers in early-stage PD patients from PPMI. In advanced PD patients from PPMI, the BJLOT, HVLT retention and SDMT scores seem to be lower in ApoEε4 carriers without reach the statistical significance. CONCLUSIONS: APOEε4 carriage does not affect the cognitive performance of early-stage PD patients. However, it may promote the decline of CSF Aß42 level and the associated amyloidopathy, which is likely to further contribute to the cognitive dysfunction of PD patients in the advanced stage.
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Cognición , Genotipo , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/fisiopatología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Cognición/fisiología , Disfunción Cognitiva/genética , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Apolipoproteínas E/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E4/genéticaRESUMEN
As pure antipodes may differ in biological interactions, pharmacology, and toxicity, discrimination of enantiomers is important in the pharmaceutical and agrochemical industries. Two major challenges in enantiomer determination are transducing and amplifying the distinct chiral-recognition signals. In this study, a light-sensitive organic photoelectrochemical transistor (OPECT) with homochiral character is developed for enantiomer discrimination. Demonstrated with the discrimination of glucose enantiomers, the photoelectrochemically active gate electrode is prepared by integrating Au nanoparticles (AuNPs) and a chiral Cu(II)-metal-organic framework (c-CuMOF) onto TiO2 nanotube arrays (TNT). The captured glucose enantiomers are oxidized to hydrogen peroxide (H2O2) by the oxidase-mimicking AuNPs-loaded c-CuMOF. Based on the confinement effect of the mesopocket structure of the c-CuMOF and the remarkable charge transfer ability of the 1D nanotubular architecture, variations in H2O2 yield are translated into significant changes in OPECT drain currents (ID) by inducing a catalytic precipitation reaction. Variations in ID confer a sensitive discrimination of glucose enantiomers with a limit of detection (LOD) of 0.07 µM for L-Glu and 0.05 µM for D-Glu. This enantiomer-driven gate electrode response strategy not only provides a new route for enantiomer identification, but also helps to understand the origin of the high stereoselectivity in living systems.
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Técnicas Biosensibles , Técnicas Electroquímicas , Glucosa , Oro , Peróxido de Hidrógeno , Límite de Detección , Nanopartículas del Metal , Estructuras Metalorgánicas , Estructuras Metalorgánicas/química , Técnicas Biosensibles/instrumentación , Oro/química , Técnicas Electroquímicas/instrumentación , Estereoisomerismo , Nanopartículas del Metal/química , Glucosa/análisis , Glucosa/química , Glucosa/aislamiento & purificación , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/análisis , Titanio/química , Transistores Electrónicos , Cobre/química , Luz , Monosacáridos/análisis , Monosacáridos/química , Nanotubos/químicaRESUMEN
BACKGROUND: Circulating zinc (Zn) concentrations are lower than normal in patients with Parkinson disease (PD). It is unknown whether Zn deficiency increases the susceptibility to PD. OBJECTIVES: The study aimed to investigate the effect of dietary Zn deficiency on behaviors and dopaminergic neurons in a mouse model of PD and to explore potential mechanisms. METHODS: Male C57BL/6J mice aged 8-10 wk were fed Zn adequate (ZnA; 30 µg/g) or Zn deficient (ZnD; <5 µg/g) diet throughout the experiments. Six weeks later 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was injected to generate the PD model. Controls were injected with saline. Thus, 4 groups (Saline-ZnA, Saline-ZnD, MPTP-ZnA, and MPTP-ZnD) were formed. The experiment lasted 13 wk. Open field test, rotarod test, immunohistochemistry, and RNA sequencing were performed. Data were analyzed with t-test, 2-factor ANOVA, or Kruskal-Wallis test. RESULTS: Both MPTP and ZnD diet treatments led to a significant reduction in blood Zn concentrations (PMPTP = 0.012, PZn = 0.014), reduced total distance traveled (PMPTP < 0.001, PZn = 0.031), and affected the degeneration of dopaminergic neurons in the substantia nigra (PMPTP < 0.001, PZn = 0.020). In the MPTP-treated mice, the ZnD diet significantly reduced total distance traveled by 22.4% (P = 0.026), decreased latency to fall by 49.9% (P = 0.026), and reduced dopaminergic neurons by 59.3% (P = 0.002) compared with the ZnA diet. RNA sequencing analysis revealed a total of 301 differentially expressed genes (156 upregulated; 145 downregulated) in the substantia nigra of ZnD mice compared with ZnA mice. The genes were involved in a number of processes, including protein degradation, mitochondria integrity, and α-synuclein aggregation. CONCLUSIONS: Zn deficiency aggravates movement disorders in PD mice. Our results support previous clinical observations and suggest that appropriate Zn supplementation may be beneficial for PD.
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Desnutrición , Enfermedad de Parkinson , Ratones , Masculino , Animales , Enfermedad de Parkinson/metabolismo , Neuronas Dopaminérgicas/metabolismo , Ratones Endogámicos C57BL , Dieta , Dopamina/metabolismo , Zinc , Sustancia Negra/metabolismo , Modelos Animales de Enfermedad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacologíaRESUMEN
Background: DNA methylation plays an important role in Parkinson's disease (PD) pathogenesis. DNA methyltransferase 1 (DNMT1) is critical for maintaining DNA methylation in mammals. The link between DNMT1 polymorphisms and PD remains elusive. Methods: The DNMT1 gene contained a total of 28 single nucleotide polymorphisms (SNPs). Four representing tag-SNPs (rs16999593, rs2162560, rs11880553, and rs9305012) were identified and genotyped in a Han Chinese population comprising 712 PD patients and 696 controls. Association analyses were performed at gene-wide significance (p < 1.8 × 10-3). Results: Rs9305012, but not the other 3 tag-SNPs, was gene-wide significantly associated with PD risk (p = 0.8 × 10-3). The rs9305012/C was a protective allele against PD (p = 1.5 × 10-3, OR 0.786, 95% CI 0.677-0.912). No significant association was observed in individual genders or PD subtypes. Haplotypes of the 4 tag-SNPs showed a significant overall distribution difference between PD patients and controls (p < 1 × 10-4). The 3-allele ACC module in the order of rs2162560, rs11880553, and rs9305012 was the highest-risk haplotype associated with PD (p < 1 × 10-4, OR 2.439, 95% CI 1.563-3.704). Rs9305012 displayed certain probability to affect transcription factor binding and target gene expression based on functional annotation analyses. Conclusion: The DNMT1 variant rs9305012 together with its haplotypes may gene-wide significantly modulate PD susceptibility. Our results support a role of DNMT1 in PD pathogenesis and provide novel insights into the genetic connection in between.
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To date, it is still a challenge for high-performance photoelectrochemical (PEC) assay of low-abundance adenosine deaminase (ADA) in fundamental research and clinical diagnosis. Herein, phosphate-functionalized Pt/TiO2 (termed PO43-/Pt/TiO2) was prepared as ideal photoactive material to develop a split-typed PEC aptasensor for detection of ADA activity, coupled by a Ru(bpy)32+ sensitization strategy. We critically studied the effects of the PO43- and Ru(bpy)32+ on the detection signals, and discussed the signal-amplified mechanism. Specifically, hairpin-structured adenosine (AD) aptamer was splited into single chain via ADA-induced catalytic reaction, and subsequently hybridized with complementary DNA (cDNA, initially coating on magnetic beads). The in-situ formed double-stranded DNA (dsDNA) was further intercalated by more Ru(bpy)32+ to amplify the photocurrents. The resultant PEC biosensor showed a broader linear range of 0.05-100 U L-1 and a lower limit of detection (0.019 U L-1), which can fill the blank for analysis of ADA activity. This research would provide some valuable insights for building advanced PEC aptasensors in ADA-related research and clinical diagnosis.
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Aptámeros de Nucleótidos , Técnicas Biosensibles , Adenosina Desaminasa , Fosfatos , Titanio , Técnicas Electroquímicas , Límite de DetecciónRESUMEN
INTRODUCTION: Parkinson's disease (PD) is highly heterogeneous in manifestations and pathogenesis. Serotonergic neurotransmitter system dysfunction is frequently implicated in PD tremor. Serotonin (5-HT) content in platelets is highly correlated with that in cerebrospinal fluid. In this study, we aimed to understand whether and how platelet 5-HT content reflects tremor in PD. METHOD: A total of 139 Chinese PD patients met with inclusion criteria were recruited. Motor and non-motor scores, and disease severity were evaluated. Patients were classified into subtypes of tremor-dominant (TD) and non-tremor-dominant (NTD). Peripheral platelets were isolated, and platelet 5-HT levels were measured. RESULTS: Platelet 5-HT content was lower in PD patients of TD subtype than in NTD subtype. Multifactor risk analysis showed that this lower content was independently associated with the TD phenotype. Platelet 5-HT level was inversely correlated with total tremor score, rest tremor amplitude score, rest tremor constancy score, and index of rest tremor, but not with postural tremor score, and kinetic tremor score. CONCLUSION: The cross-sectional study demonstrates that reduced platelet 5-HT content is associated with PD rest tremor. Our results support the involvement of serotonergic disturbance in PD rest tremor and indicate that 5-HT reduction can be manifested in peripheral platelets.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Temblor/etiología , Serotonina , Estudios Transversales , FenotipoRESUMEN
Oxidative damage generally exists in stroke and impairs stem cells' survival; however, the problem is difficult to treat. In order to help stem cells to resist this damage, we inserted a magnetotactic bacteria (MB) gene, mms6, into the neural stem cell genome by lentiviral transfection. It was found that the transfection of mms6 significantly improved the survival rate of stem cells in the condition of iron overload but not hypoxia. The bioenergetic profile also revealed that iron overloading weakened the mitochondrial respiration and spare respiration capacity of stem cells, but that these were enhanced after the expression of mms6. Additionally, Western blotting (WB) data revealed that mms6 upregulated the expression of glutathione peroxidase (GPX4), which protected stem cells from oxidative damage and ferroptosis. In order to determine the possible mechanisms, we analyzed the interactions between the MMS6 protein, Fe2+, and GPX4 via analog computation. The predicted models found that the MMS6 protein had a direct chelating site in the region of M6A with divalent iron; it also had weak binding with GPX4. Taken together, the magnetotactic bacterial gene mms6 protected stem cells from oxidative damage via binding with Fe2+, which could help them adapt to the microenvironment of stroke.
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Parkinsonism-hyperpyrexia syndrome (PHS) and dyskinesia-hyperpyrexia syndrome (DHS) are rare but exhibit life-threatening complications in Parkinson's disease (PD). We herein presented two cases of PD patients and performed a comprehensive and comparative literature review for these two syndromes. The first case was diagnosed as PHS with cerebral salt wasting syndrome caused by abrupt withdrawal of antiparkinsonian medication. Her symptoms were gradually remitted with reinstitution of the medication. The second one was an early-stage PD patient diagnosed as DHS in association with abuse of antiparkinsonian drugs. Her symptoms were gradually remitted with reduced dosage of dopaminergic drugs. Results of literature reviews revealed a total of 56 and 13 cases of PHS and DHS, respectively, and they were more likely to occur in elderly and long-term PD patients. These two syndromes showed different female-to-male ratio, similar mortality, and different recovery time. There were stark differences between PHS and DHS, including triggers (abrupt drug stoppage versus drug abuse), symptoms (worsened tremor and rigidity versus continuous dyskinesia), and treatment (drug reinstitution versus drug reduction). In summary, our reports and the review provide new insights into PHS and DHS in association with PD and may facilitate rapid discrimination of the syndromes for timely and proper treatment to reduce mortality.
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Enfermedad de Parkinson , Trastornos Parkinsonianos , Anciano , Antiparkinsonianos/uso terapéutico , Femenino , Humanos , Levodopa , Masculino , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/tratamiento farmacológico , Síndrome , Temblor/complicacionesRESUMEN
Background: Environmental substances such as pesticides are well-known in link with Parkinson's disease (PD) risk. Enzymes including cytochromes P450 (CYPs), esterases and glutathione S-transferases (GSTs) are responsible for the xenobiotic metabolism and may functionally compensate each other for subtypes in the same class. We hypothesize that the genetic effects of each class modulate PD risk stronger in a synergistic way than individually. Methods: We selected 14 polymorphic loci out of 13 genes which encode enzymes in the classes of CYP, esterase, and GST, and recruited a cohort of 1,026 PD and control subjects from eastern China. The genotypes were identified using improved multiplex ligation detection reaction and analyzed using multiple models. Results: A total of 13 polymorphisms remained after Hardy-Weinberg equilibrium analysis. None of the polymorphisms were independently associated with PD risk after Bonferroni correction either by logistic regression or genetic models. In contrast, interaction analyses detected increased resistance to PD risk in individuals carrying the rs12441817/CC (CYP1A1) and rs2070676/GG + GC (CYP2E1) genotypes (P = 0.002, OR = 0.393, 95% CI = 0.216-0.715), or carrying the GSTM1-present, GSTT1-null, rs156697/AG + GG (GSTO2) and rs1695/AA (GSTP1) genotypes (P = 0.003, OR = 0.348, 95% CI = 0.171-0.706). The synergistic effect of GSTs on PD was primarily present in females (P = 0.003). No synergistic effect was observed within genotypes of esterases. Conclusion: We demonstrate a presence of synergistic but not individual impact on PD susceptibility in polymorphisms of CYPs and GSTs. The results indicate that the genetic interplay leads the way to PD development for xenobiotic metabolizing enzymes.
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BACKGROUND: Aldehyde dehydrogenase 1 (encoded by ALDH1A1) has been shown to protect against Parkinson's disease (PD) by reducing toxic metabolites of dopamine. We herein revealed an antisense Alu element insertion/deletion polymorphism in intron 4 of ALDH1A1, and hypothesized that it might play a role in PD. METHODS: A Han Chinese cohort comprising 488 PD patients and 515 controls was recruited to validate the Alu insertion/deletion polymorphism following a previous study of tag-single nucleotide polymorphisms, where rs7043217 was shown to be significantly associated with PD. Functional analyses of the Alu element insertion were performed. RESULTS: The Alu element of ALDH1A1 was identified to be a variant of Yb8 subfamily and termed as Yb8c4. The antisense Yb8c4 insertion/deletion polymorphism (named asYb8c4ins and asYb8c4del, respectively) appeared to be in a complete linkage disequilibrium with rs7043217 and was validated to be significantly associated with PD susceptibility with asYb8c4ins serving as a risk allele (P = 0.030, OR = 1.224, 95% CI = 1.020-1.470). Multiple functional analyses including ALDH1A1 mRNA expression in blood cells of carriers, and reporters of EGFP and luciferase showed that the asYb8c4ins had a suppressive activity on gene transcription. Mechanistic explorations suggested that the asYb8c4ins induced no changes in CpG methylation and mRNA splicing of ALDH1A1 and appeared no binding of transcription factors. CONCLUSIONS: Our results consolidate an involvement of ALDH1 in PD pathogenesis. The asYb8c4 polymorphism may be a functional output of its linkage disequilibrium-linked single nucleotide polymorphisms.
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Enfermedad de Parkinson , Familia de Aldehído Deshidrogenasa 1 , Pueblo Asiatico/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero , Retinal-Deshidrogenasa/genéticaRESUMEN
CLEC16A is a membrane-associated endosomal protein implicated in regulating autophagy and antigen presentation. Its genetic variants are broadly associated with multiple autoimmune diseases. Parkinson's disease (PD), which undergoes autophagy disruption and neuroinflammation, has been clinically observed, for an extensive amount of time, to be associated with autoimmune diseases. In this study, we aimed to understand whether the autoimmune disease associated CLEC16A variants pleiotropically modulate PD risk. Five of such CLEC16A variants, including rs6498169, rs12708716, rs12917716, rs7200786, and rs2903692, were selected and analyzed in a Han Chinese cohort comprising 515 sporadic PD patients and 504 controls. Results showed that rs6498169 and rs7200786 were significantly associated with PD susceptibility (p = 0.005 and 0.004, respectively; recessive model, p = 0.002 and 0.001, respectively). Rs6498169 was also associated with the PD subtype of postural instability/gait difficulty (p = 0.002). Haplotype analysis showed that the AAG module in order of rs6498169, rs12708716, and rs2903692 was associated with the highest risk for PD (p = 0.0047, OR = 1.42, 95% CI = 1.11-1.82). Functional annotation analyses suggested that rs6498169 had high probability to affect transcription factor binding and target gene expression. In summary, the current study demonstrates that the autoimmune disease associated CLEC16A variants convey risk of PD in Han Chinese. Our findings suggest a pleiotropic role of CLEC16A and strengthen the link between PD and autoimmune diseases.
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Enzyme-mediated signal amplification strategies have gained substantial attention in photoelectrochemical (PEC) biosensing, while natural enzyme on the photoelectrode inevitably obstructs the interfacial electron transfer, in turn deteriorating the photocurrent responses. Herein, Au nanoparticles and Cu2+-modified boron nitride nanosheets (AuNPs/Cu2+-BNNS) behaved as nanozyme to achieve remarkable magnification in the PEC signals from a novel signal-off aptasensor for ultra-sensitive assay of telomerase (TE) activity based on Ag2S/Ag nanoparticles decorated ZnIn2S4/C3N4 Z-scheme heterostructures (termed as Ag2S/Ag/ZnIn2S4/C3N4, synthesized by hydrothermal treatment). Specifically, telomerase primer sequences (TS) were extended by TE in the presence of deoxyribonucleoside triphosphates (dNTPs), which was directly bond with the thiol modified complementary DNA (cDNA), achieving efficient linkage with the nanozyme via Au-S bond. The immobilized nanoenzyme catalyzed the oxidation between 4-chloro-1-naphthol (4-CN) and H2O2 to generate insoluble precipitation on the photo-electrode. By virtue of the inhibited PEC signals with the TE-enabled TS extension, an aptasensor for assay of TE activity was developed, showing the wide linear range of 50-5×105 cell mL-1 and a low detection limit of 19 cell mL-1. This work provides some valuable guidelines for developing advanced nanozyme-based PEC bioanalysis of diverse cancer cells.
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Técnicas Biosensibles , Nanopartículas del Metal , Telomerasa , Boro , Compuestos de Boro , Técnicas Electroquímicas , Oro/química , Peróxido de Hidrógeno , Límite de Detección , Nanopartículas del Metal/química , PlataRESUMEN
Carbon-coated cadmium sulfide rose-like nanostructures (CdS@C NRs) were prepared via a facile solvothermal approach and used as the photoelectrochemical (PEC) sensing platform for the integration of functional biomolecules. Based on this, a novel "signal-off" PEC aptasensor mediated by enzymatic amplification was proposed for the sensitive and selective detection of 17ß-estradiol (E2). In the presence of E2, alkaline phosphatase-modified aptamer (ALP-apta) were released from the electrode surface through the specific recognition with E2, which caused the negative effect on PEC response due to the decrease of ascorbic acid (AA) produced by the ALP in situ enzymatic catalysis. The developed PEC aptasensor for detection of E2 exhibited a wide linear range of 1.0-250 nM, with the low detection limit of 0.37 nM. This work provides novel insight into the design of potential phoelectroactive materials and the application of signal amplification strategy in environmental analysis field.
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Compuestos de Cadmio/química , Carbono , Enzimas/metabolismo , Estradiol/química , Nanoestructuras/química , Procesos Fotoquímicos , Sulfuros/química , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Enzimas/química , Microscopía Electrónica de RastreoRESUMEN
Parkinson's disease (PD) is associated with α-synuclein-based Lewy body pathology, which has been difficult to observe in conventional two-dimensional (2D) cell culture and even in animal models. We herein aimed to develop a three-dimensional (3D) cellular model of PD to recapitulate the α-synuclein pathologies. All-trans-retinoic acid-differentiated human SH-SY5Y cells and Matrigel were optimized for 3D construction. The 3D cultured cells displayed higher tyrosine hydroxylase expression than 2D cells and improved dopaminergic-like phenotypes, as suggested by RNA-sequencing analyses. Multiple forms of α-synuclein, including monomer, and low- and high-molecular mass oligomers, were differentially present in the 2D and 3D cells, but mostly remained unchanged upon N-methyl-4-phenyl pyridine or rotenone treatment. Phosphorylated α-synuclein was accumulated, and detergent-insoluble α-synuclein fraction was observed, in the neurotoxin-treated 3D cells. Importantly, Lewy body-like inclusions were captured in the 3D system, including proteinase K-resistant α-synuclein aggregates, ubiquitin aggregation, and ß-amyloid and ß-sheet protein deposition. The study provides a unique and convenient 3D model of PD that recapitulates critical α-synuclein pathologies and should be useful in multiple PD-associated applications.
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Enfermedad de Parkinson , Línea Celular Tumoral , Colágeno , Combinación de Medicamentos , Humanos , Laminina/metabolismo , Cuerpos de Lewy/metabolismo , Enfermedad de Parkinson/patología , Proteoglicanos , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND: Genome-wide association studies for neuromyelitis optica spectrum disorder (NMOSD) have established an association between HLA-DQ alpha 1 (DQA1) and risk for NMOSD. Though ethnicity is generally considered a major influencing factor in genetic analyses, little is known regarding the association of HLA-DQA1 polymorphisms with NMOSD in the Han population, especially the single-nucleotide polymorphisms (SNPs) at HLA-DQA1 . METHODS: We genotyped SNP at loci rs28383224 in a case-control study consisting of 137 subjects (51 patients with NMOSD and 86 unrelated controls were recruited) of Han ethnicity. Logistic regression was used to test the association of SNP with NMOSD susceptibility, the sex and age were adjusted, odds ratios and 95% confidence intervals were estimated. RESULTS: The rs28383224 polymorphism and susceptibility to NMOSD were not statistically associated ( P >0.05) in the Han population in the current study. No significant difference was found in allelic frequencies or genotypic distributions among different subsets of NMOSD patients ( P >0.05). CONCLUSION: In the current study, there is no evidence that polymorphism of rs28383224 in the HLA-DQA1 gene is associated with the risk of NMOSD in the Han Chinese population.
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Neuromielitis Óptica , Estudios de Casos y Controles , China , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Antígenos HLA-DQ/genética , Cadenas alfa de HLA-DQ , Humanos , Neuromielitis Óptica/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Background: Studies in animal models have suggested that aldehyde dehydrogenase 1 (encoded by ALDH1A1) protects against Parkinson's disease (PD) by reducing toxic metabolites of dopamine. Herein we aimed to investigate whether ALDH1A1 was genetically associated with PD susceptibility in humans. Methods: A Han Chinese population of 1,039 subjects was recruited to analyze six tag-single nucleotide polymorphisms (SNPs), followed by haplotype analyses and variants interaction analyses. Real-time PCR was used to analyze mRNA levels of ALDH1A1 in peripheral blood of 42 subjects. Results: The tag-SNP rs7043217 of ALDH1A1 was significantly associated with PD susceptibility with the T serving as a risk allele (genotype frequency, P = 0.030; allele frequency, P = 0.013, OR = 1.258, 95% CI = 1.050-1.508). Multiple haplotypes were linked to abnormalities of PD risk, topped by a 4-SNP GGTA module in the order of rs4646547, rs1888202, rs7043217, and rs647880 (P = 9.610 × 10-8, OR = 6.420, 95% CI = 2.944-13.998). Interaction analyses showed that a simultaneous presence of the CC genotype of rs7043217 and the TT genotype of ALDH2 variant rs4767944 conferred an elevated protection against PD (P = 4.68 × 10-4, OR = 0.378, 95% CI = 0.219-0.652). The mRNA expression of ALDH1A1 showed a trend of reduction (P = 0.084) in PD patients compared to the controls. Conclusion: Our results provide novel genetic insights into the role of ALDH1 in PD pathogenesis.
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Severe challenges are still remained for development of highly sensitive, selective and stable photoelectrochemical (PEC) sensing technology, albeit with its broad application for chloramphenicol (CAP) detection. Herein, a novel "signal-on" PEC aptasensor was fabricated based on a 3D self-supporting Z-scheme AgI/Ag/BiOI heterojunction arrays subtly integrated with in-situ formed biocatalytic precipitation (BCP) for highly sensitive and selective determination of CAP. Impressively, the HRP modified CAP aptamer (HRP-CAP aptamer) was released from the electrode by its strong affinity to the introduced CAP, and gradually terminated the BCP reaction, in turn recovering the photocurrent. By virtues of the 3D self-supporting AgI/Ag/BiOI Z-scheme heterojunction arrays and BCP signal amplification strategy, the resultant PEC sensor exhibited a wide linear range of 2-250 nM with a limit of detection (LOD) as low as 0.226 nM (S/N = 3). This work opens a new avenue for design of PEC aptasensing strategy and exhibits the marvelous potential in bioanalysis of environmental samples.
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Aptámeros de Nucleótidos , Técnicas Biosensibles , Cloranfenicol , Técnicas Electroquímicas , PlataRESUMEN
BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants. METHODS: Primary astrocytes were isolated and cultured using neurobasal-based serum-free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α, and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed. RESULTS: All the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1ß (IL-1ß). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1ß but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity. CONCLUSIONS: The study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.
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Antidepresivos/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Animales Recién Nacidos , Antidepresivos/toxicidad , Astrocitos/patología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/toxicidadRESUMEN
Aberrant DNA methylation is closely associated with the pathogenesis of Parkinson's disease (PD). DNA methyltransferases (DNMTs) are the enzymes for establishment and maintenance of DNA methylation patterns. It has not been clearly defined how DNMTs respond in PD and what mechanisms are associated. Models of PD were established by treatment of five different neurotoxins in cells and intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Plasma samples of PD patients were also used. Western blot, real-time PCR, immunostaining, and/or luciferase reporter were employed. DNA methylation was analyzed by the bisulfite sequencing analysis. Protein expression of DNMT1, but not of DNMT3A and DNMT3B, was reduced in the cellular and mouse models of PD. Paradoxically, mRNA levels of DNMT1 were increased in these models. After ruling out the possibility of protein degradation, we screened a set of miRNAs that potentially targeted DNMT1 3'-UTR by luciferase reporters and expression abundancies. miR-17 was identified for further investigation with miR-19a of low expression as a parallel comparison. Although exogenous transfection of either miR-17 or miR-19a mimics could inhibit DNMT1 expression, results of miRNA inhibitors showed that miR-17, but not miR-19a, endogenously regulated DNMT1 and the subsequent DNA methylation. Furthermore, levels of miR-17 were elevated in the neurotoxin-induced PD models and the plasma of PD patients. This study demonstrates that the miR-17-mediated DNMT1 downregulation underlies the aberrant DNA methylation in PD. Our results provide a link bridging environmental insults and epigenetic changes and implicate miR-17 in therapeutical modulation of DNA methylation in PD.