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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: Congenital sideroblastic anemia (CSA) is a rare and heterogeneous group of genetic disorders. Conventional treatment include pyridoxine (vitamin B6) and allogeneic hematopoietic stem cell transplantation (allo-HSCT), and can alleviate anemia in the majority of cases. Nevertheless, some CSA cases remain unresponsive to pyridoxine or are unable to undergo allo-HSCT. Novel management approaches is necessary to be developed. To explore the response of luspatercept in treating congenital sideroblastic anemia. CASE SUMMARY: We share our experience in luspatercept in a 4-year-old male patient with CSA. Luspatercept was administered subcutaneously at doses of 1.0 mg/kg/dose to 1.25 mg/kg/dose every 3 wk, three consecutive doses, evaluating the hematological response. Luspatercept leading to a significant improvement in the patient's anemia. The median hemoglobin during the overall treatment with three doses of luspatercept was 90 (75-101) g/L, the median absolute reticulocyte count was 0.0593 (0.0277-0.1030) × 1012/L, the median serum ferritin was 304.3 (234.4-399) ng/mL, and the median lifespan of mature red blood cells was 80 (57-92) days. Notably, no adverse reactions, such as headaches, dizziness, vomiting, joint pain, or back pain, were observed during the treatment period. CONCLUSION: We believe that luspatercept might emerge as a viable therapeutic option for the maintenance treatment of CSA or as a bridging treatment option before hematopoietic stem cell transplantation.
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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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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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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
OBJECTIVE: To explore the relationship between the change of lymphocyte subsets before and after immunosuppressive therapy (IST) with disease severity of severe aplastic anemia (SAA) and hematologic response to IST. METHODS: The clinical data of 94 patients with SAA/VSAA treated by r-ATG and CsA in our hospital from December 2009 to October 2011 was analyzed retrospectively. Among them, 26 patients who had sequential data of lymphocyte subsets and cytokines before and after treatment were enrolled. The relationship between lymphocyte subsets, cytokine level before IST and disease severity, as well as the relationship between changes if lymphocyte subsets, changes of cytokine and the HR after IST for 6 months was analyzed. RESULTS: There were no statistical differences in the ratio and absolute count of lymphocyte, the ratio and absolute count of each lymphocyte subsets, including CD3+T cells, CD3+CD4+T cells, CD3+CD8+T cells, CD3-CD16+1CD56+NK cells, and CD19+B cells, and the level of cytokines, such as IL-1, IL-2, IL-4, IL-6 and TNF-α before IST between SAA and VSAA groups. Also, there were no statistical difference in the levels of above-motional parameter at 3 and 6 months after IST. The ratio and absolute count of Lym, absolute count of CD3+T cells, absolute count of B cells and IL-2 level in response group after IST for 3 and 6 months was significant lower than those before IST. However, only ratio of Lym showed significant decrease after IST for 3 and 6 months in non-response group. After IST for 3 months, the absolute count of CD3+T and CD4+T cells in response group was significant higher than those in non-response group. CONCLUSION: The hematopoietic recovery and early hematologic remission may be affected by the intensity of immune suppression reflected from the changes of lymphocyte subsets and the immune reconstruction reflected from the recovery of lymphocyte subsets. The immune reconstruction is most significant within 3 months after IST.
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Anemia Aplásica , Humanos , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Subgrupos Linfocitarios , Estudios RetrospectivosRESUMEN
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.
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ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , MicroARNs/metabolismo , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/genética , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasa 1/genética , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Lisosomas/metabolismo , Masculino , Ratones Endogámicos C57BL , MicroARNs/genética , Modelos Biológicos , Neurotoxinas/toxicidad , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Hereditary spherocytosis (HS) is a hereditary disease of hemolytic anemia that occurs due to the erythrocyte membrane defects. Dubin-Johnson syndrome (DJS), which commonly results in jaundice, is a benign hereditary disorder of bilirubin clearance that occurs only rarely. The co-occurrence of HS and DJS is extremely rare. We recently diagnosed and treated a case of co-occurring HS and DJS. CASE SUMMARY: A 21-year-old female patient presented to our department because of severe jaundice, severe splenomegaly, and mild anemia since birth. We eventually confirmed the diagnosis of co-occurring DJS and HS by next generation sequencing (NGS). The treatment of ursodeoxycholic acid in combination with phenobarbital successfully increased hemoglobin and reduced total bilirubin and direct bilirubin. CONCLUSION: The routine application of NGS can efficiently render a definite diagnosis when inherited disorders are suspected.
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BACKGROUND: Selenium is prioritized to the brain mainly for selenoprotein expression. Selenoprotein T (SELENOT) protects dopaminergic, postmitotic neurons in a mouse model of Parkinson's disease (PD). OBJECTIVE: We hypothesized a proliferative role of SELENOT in neural cells. METHODS: To assess SELENOT status in PD, sedated male C57BL/6 mice at 10-12 wk of age were injected with 6-hydroxydopamine in neurons, and human peripheral blood mononuclear cells were isolated from 9 healthy subjects (56% men, 68-y-old) and 11 subjects with PD (64% men, 63-y-old). Dopaminergic neural progenitor-like SK-N-SH cells with transient SELENOT overexpression or knockdown were maintained in the presence or absence of the antioxidant N-acetyl-l-cysteine and the calcium channel blocker nimodipine. Cell cycle, proliferation, and signaling parameters were determined by immunoblotting, qPCR, and flow cytometry. RESULTS: SELENOT mRNA abundance was increased (P < 0.05) in SK-N-SH cells treated with 1-methyl-4-phenylpyridinium iodide (3.5-fold) and peripheral blood mononuclear cells from PD patients (1.6-fold). Likewise, SELENOT was expressed in tyrosine hydroxylase-positive dopaminergic neurons of 6-hydroxydopamine-injected mice. Knockdown of SELENOT in SK-N-SH cells suppressed (54%; P < 0.05) 5-ethynyl-2'-deoxyuridine incorporation but induced (17-47%; P < 0.05) annexin V-positive cells, CASPASE-3 cleavage, and G1/S cell cycle arrest. SELENOT knockdown and overexpression increased (88-120%; P < 0.05) and reduced (37-42%; P < 0.05) both forkhead box O3 and p27, but reduced (51%; P < 0.05) and increased (1.2-fold; P < 0.05) cyclin-dependent kinase 4 protein abundance, respectively. These protein changes were diminished by nimodipine or N-acetyl-l-cysteine treatment (24 h) at steady-state levels. While the N-acetyl-l-cysteine treatment did not influence the reduction in the amount of calcium (13%; P < 0.05) by SELENOT knockdown, the nimodipine treatment reversed the decreased amount of reactive oxygen species (33%; P < 0.05) by SELENOT overexpression. CONCLUSIONS: These cellular and mouse data link SELENOT to neural proliferation, expanding our understanding of selenium protection in PD.
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Proliferación Celular/fisiología , Fase G1/fisiología , Enfermedad de Parkinson/patología , Fase S/fisiología , Selenoproteínas/fisiología , Anciano , Animales , Calcio/metabolismo , Línea Celular , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia ArribaRESUMEN
Genetics is a branch of biology that studies the laws of inheritance and variation from the level of genes (genomes). Genetics teaching should be compatible with the evolving genetic disciplines and social needs. In view of the continuous development of the genetics knowledge system and the requirements for the training of biological students, our teaching team carried out the curriculum design and implementation of genetics blended course under the principle of constructive alignment. The reform actions include: (1) constructing genetics online resources with genetic analysis as the main line; (2) optimizing the learning objectives according to bloom's educational goals classification; (3) designing learning activities and learning assessments under the principle of constructive alignment; (4) enrich the forms of learning activities, highlighting learning-centered course design and learner interaction, promoting active learning, and improving learning outcomes. The results of the questionnaire survey and exam result analysis suggest that the blended course reform has achieved initial results. The course is fully affirmed by the students and helps to improve learning outcomes, which is worthy of further consolidation and promotion. This paper generally introduces the curriculum design and preliminary practice of genetics blended course, providing new insights and approaches for the continued development of genetics teaching in the new era.
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Curriculum , Genética/educación , Humanos , Investigación , Estudiantes , EnseñanzaRESUMEN
A recent large-scale European-originated genome-wide association data meta-analysis followed by a replication study identified 6 new risk loci for Parkinson's disease (PD), which include rs10797576/SIPA1L2, rs117896735/INPP5F, rs329648/MIR4697, rs11158026/GCH1, rs2414739/VPS13C, and rs8118008/DDRGK1. However, whether these new loci are associated with PD in Asian populations remain elusive. The INPP5F is nonpolymorphic in Asians. The present study aimed to understand the effects of the other 5 new loci in a Han Chinese population comprising 579 sporadic PD patients and 642 controls. Significant associations with PD were observed in the variants of SIPA1L2 (p = 0.001) and VPS13C (p = 0.007), where the T (odd ratio [OR] = 1.484, 95% confidence interval [CI] 1.186-1.858) and A (OR = 1.362, 95% CI 1.087-1.707) alleles serve as the risk alleles, respectively. The genotype distributions in the SIPA1L2 and VPS13C variants were also different between the patients and controls (p = 0.002 and p = 0.023, respectively). In contrast, no significant association with PD was found in the variants of MIR4697, GCH1, and DDRGK1 either in allele or genotype frequencies. Noteworthy, a followed meta-analysis of East Asian studies suggested an association of the GCH1 variant with PD (p = 0.04, OR 1.08, 95% CI 1.00-1.16), while the other results are in line with those of our cohort. In conclusion, our study together with meta-analyses demonstrates that the variants of SIPA1L2 and VPS13C, potentially GCH1, but not of MIR4697 and DDRGK1, are associated with PD susceptibility in East Asians.
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Proteínas Portadoras/genética , GTP Ciclohidrolasa/genética , Proteínas Activadoras de GTPasa/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo , MicroARNs/genética , Proteínas Nucleares/genética , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/genética , Proteínas/genética , Proteínas Adaptadoras Transductoras de Señales , Anciano , Pueblo Asiatico/genética , Asia Oriental , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUNDS: Long non-coding RNA (LncRNA) have been reported to be involved in the pathogenesis of neurodegenerative diseases, but whether it can serve as a biomarker for Alzheimer disease (AD) is not yet known. METHODS: The present study selected four specific LncRNA (17A, 51A, BACE1 and BC200) as possible AD biomarker. RT-qPCR was performed to validate the LncRNA. Receiver operating characteristic curve (ROC) and area under the ROC curve (AUC) were applied to study the potential of LncRNA as a biomarker in a population of 88 AD patients and 72 control individuals. RESULTS: We found that the plasma LncRNA BACE1 level of AD patients was significantly higher than that of healthy controls (p = 0.006). Plasma level of LncRNA 17A, 51A and BC200 did not show a significant difference between two groups (p = 0.098, p = 0.204 and p = 0.232, respectively). ROC curve analysis showed that LncRNA BACE1 was the best candidate of these LncRNA (95% CI: 0.553-0.781, p = 0.003). In addition, no correlation was found for expression of these LncRNA in both control and AD groups with age or MMSE scale (p > 0.05). CONCLUSIONS: Our present study compared the plasma level of four LncRNA between AD and non-AD patients, and found that the level of the BACE1 is increased in the plasma of AD patients and have a high specificity (88%) for AD, indicating BACE1 may be a potential candidate biomarker to predict AD.
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Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Biomarcadores/sangre , ARN Largo no Codificante , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/sangre , Secretasas de la Proteína Precursora del Amiloide/genética , Ácido Aspártico Endopeptidasas/sangre , Ácido Aspártico Endopeptidasas/genética , Estudios de Casos y Controles , Humanos , ARN Largo no Codificante/sangre , ARN Largo no Codificante/genética , Curva ROCRESUMEN
Hyperoside (quercetin-3-O-ß-d-galactoside) is an active compound isolated from herbs. Neuroinflammation is a key mechanism involved in neurodegenerative disorders including Parkinson's disease. In this study, we aimed to investigate the potentiality of hyperoside in inhibiting microglia-mediated neuroinflammation. BV2 microglial cells were pretreated with hyperoside and stimulated with lipopolysaccharide (LPS). The results showed that hyperoside significantly inhibited LPS-induced production of nitric oxide and pro-inflammatory cytokines including IL-1ß and TNF-α, as well as the expression of inducible nitric oxide synthase. Similar results were observed in primary microglial cells isolated from neonatal mice. Analyses in MAPK and NFκB signaling combined with specific inhibitors suggested that hyperoside attenuated the LPS-induced inflammatory responses via p38 and NFκB pathways. Furthermore, hyperoside suppressed reactive microglia-mediated neurotoxicity as evidenced by conditioned media culture, but had no direct impact on MPP+-induced toxicity in SH-SY5Y neuroblastoma cells. Collectively, our data suggest that hyperoside may serve as a protective agent by alleviating microglia activation in disorders such as Parkinson's disease.
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Antiinflamatorios/farmacología , Microglía/efectos de los fármacos , Neuroblastoma/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Inflamación Neurogénica/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Quercetina/análogos & derivados , Animales , Línea Celular Tumoral , Interleucina-1beta/metabolismo , Lipopolisacáridos/inmunología , Ratones , Microglía/inmunología , Neuroblastoma/inmunología , Enfermedades Neurodegenerativas/inmunología , Inflamación Neurogénica/inmunología , Óxido Nítrico/metabolismo , Enfermedad de Parkinson/inmunología , Quercetina/farmacología , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Tumor-associated macrophages are key regulators of the complex interplay between tumor and tumor microenvironment. M2 Macrophages, one type of tumor-associated macrophages, are involved in prostate cancer growth and progression. Protein kinase C zeta has been shown to suppress prostate cancer cell growth, invasion, and metastasis as a tumor suppressor; however, its role in chemotaxis and activation of tumor-associated macrophages remains unclear. Here, we investigated the role of protein kinase C zeta of prostate cancer cells in regulation of macrophage chemotaxis and M2 phenotype activation. Immunohistochemistry was performed to analyze the expression of protein kinase C zeta and the number of CD206+ M2 macrophages in human prostate tissue. Macrophage chemotaxis and polarization were examined using Transwell migration assays and a co-culture system. Quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were used to detect M2 markers, protein kinase C zeta, interleukin-4, and interleukin-10 expression. We found the expression of protein kinase C zeta increased in prostate cancer tissues, especially in the early stage, and was negatively associated with tumor grade and the number of CD206+ macrophages. Inhibition of protein kinase C zeta expression in prostate cancer cells promoted chemotaxis of peripheral macrophages and acquisition of M2 phenotypic features. These results were further supported by the finding that silencing of endogenous protein kinase C zeta promoted the expression of prostate cancer cell-derived interleukin-4 and interleukin-10. These results suggest that protein kinase C zeta plays an important role in reducing infiltration of tumor-associated macrophages and activation of a pro-tumor M2 phenotype, which may constitute an important mechanism by which protein kinase C zeta represses cancer progression.
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Interleucina-10/biosíntesis , Interleucina-4/biosíntesis , Neoplasias de la Próstata/genética , Proteína Quinasa C/biosíntesis , Línea Celular Tumoral , Proliferación Celular/genética , Quimiotaxis/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-10/genética , Interleucina-4/genética , Lectinas Tipo C/genética , Macrófagos/metabolismo , Masculino , Receptor de Manosa , Lectinas de Unión a Manosa/genética , Clasificación del Tumor , Estadificación de Neoplasias , Próstata/metabolismo , Próstata/patología , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/genética , Receptores de Superficie Celular/genética , Microambiente Tumoral/genéticaRESUMEN
Genes of selenoproteome have been increasingly implicated in various aspects of neurobiology and neurological disorders, but remain largely elusive in Parkinson's disease (PD). In this study, we investigated the selenotranscriptome (24 selenoproteins in total) in five brain regions (cerebellum, substantia nigra, cortex, pons and hippocampus) by real time qPCR in a two-phase manner using a mouse model of chronic PD. A wide range of changes in selenotranscriptome was observed in a manner depending on selenoproteins and brain regions. While Selv mRNA was not detectable and Dio1& 3 mRNA levels were not affected, 1, 11 and 9 selenoproteins displayed patterns of increase only, decrease only, and mixed response, respectively, in these brain regions of PD mice. In particular, the mRNA expression of Gpx1-4 showed only a decreased trend in the PD mouse brains. In substantia nigra, levels of 17 selenoprotein mRNAs were significantly decreased whereas no selenoprotein was up-regulated in the PD mice. In contrast, the majority of selenotranscriptome did not change and a few selenoprotein mRNAs that respond displayed a mixed pattern of up- and down-regulation in cerebellum, cortex, hippocampus, and/or pons of the PD mice. Gpx4, Sep15, Selm, Sepw1, and Sepp1 mRNAs were most abundant across all these five brain regions. Our results showed differential responses of selenoproteins in various brain regions of the PD mouse model, providing critical selenotranscriptomic profiling for future functional investigation of individual selenoprotein in PD etiology.
RESUMEN
To investigate the soil phosphorus forms and leaching risk in a typically agricultural catchment of Ershibu River in Hefei Suburban, Chaohu Lake basin, 132 surface soil samples were collected from the catchment area. The spatial distribution of total phosphorus (TP) and bio-available phosphorus (Bio-P), and the spatial variability of soil available phosphorus (Olsen-P) and easy desorption phosphorus (CaCl2-P) were analyzed using the Kriging technology of AreGIS after speciation analysis of soil phosphorus. Moreover, the enrichment level of soil phosphorus was studied, and the phosphorus leaching risk was evaluated through determining the leaching threshold value of soil phosphorus. The results showed that the samples with high contents of TP and Bio-P mainly located in the upstream of the left tributary and on the right side of local area where two tributaries converged. The enrichment rates of soil phosphorus forms were arranged as follows: Ca-P (15.01) > OP (4.16) > TP (3. 42) > IP (2.94) > Ex-P (2.76) > Fe/Al-P (2.43) > Olsen-P (2.34). The critical value of Olsen-P leaching was 18.388 mg x kg(-1), and the leaching samples with values higher than the threshold value accounted for 16.6% of total samples. Generally, the high-risk areas mainly occurred in the upstream of the left tributary, the middle of the right tributary and the local area of the downstream of the area where two tributaries converged.
Asunto(s)
Agricultura , Fósforo/química , Contaminantes del Suelo/análisis , Suelo/química , China , Análisis EspacialRESUMEN
OBJECTIVE: To evaluate the value of serum soluble transferrin receptor (sTfR) concentration in predicting early response to immunosuppressive therapy (IST) in severe aplastic anemia (SAA). METHODS: Clinical data and hematologic responses of 140 SAA patients treated with rabbit antithymocyte globulin (rATG) combination with cyclosporine in our hospital were retrospectively analyzed. Correlation of pre-IST baseline of sTfR and IST responses was statistically analyzed and receiver operating characteristic (ROC) curve was used to estimate the sensitivity and specificity of sTfR in prediction of early responses. RESULTS: Serum concentration of sTfR in very SAA (VSAA) patients were significantly lower than SAA and transfusion dependent non-SAA cases (P=0.001). The responders, especially at 3 months, had significantly higher pre- IST baseline of sTfR [median, 0.89 (range, 0.21-2.42) mg/L] than that [median, 0.58 (range, 0.13-1.88) mg/L] of non-responders (P=0.005). The cutoff level of 0.91 mg/L and 0.88 mg/L for predicting responses at 3 and 6 months were established based on the ROC curve, with the degree of accuracy of 65.0% and 60.7% respectively. Multivariate analysis showed that pre-IST baseline of sTfR was the independent factor of predicting response at 3 months (P=0.007) and at 6 months (P=0.021). CONCLUSION: As a indicator of bone marrow failure severity, sTfR could predict early response to IST therapy in aplastic anemia.
Asunto(s)
Anemia Aplásica/terapia , Terapia de Inmunosupresión , Receptores de Transferrina/uso terapéutico , Adolescente , Adulto , Anciano , Suero Antilinfocítico/uso terapéutico , Niño , Preescolar , Ciclosporina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Transferrina/inmunología , Estudios Retrospectivos , Sensibilidad y Especificidad , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To investigate the clinical features and therapeutic method for severe aplastic anemia (SAA) associated with ß-thalassemia, and to improve the recognition of the disease. METHODS: One patient hospitalized for pancytopenia was reported and the related literatures were reviewed. RESULTS: A 14-years old girl who presented with anemia from her childhood was hospitalized for acute onset of pancytopenia. Routine blood test showed that WBC count was 1.28×109/L, hemoglobin 65 g/L, platelet count 18×109/L, reticulocyte count 2×109/L, neutrophil count 0.03×109/L and mean corpuscular volume 59.6 fl, respectively. Both bone marrow aspiration and biopsy showed hypoplasia. Her red blood cells presented as microcytic hypochromic and target erythrocytes were common on peripheral blood smear. DNA analysis of the patient and her mother showed exon 17 heterozygous ß-thalassemia (c.52 A>T). A diagnosis of SAA associated with ß-thalassemia was clarified and high-dose cyclophosphamide (HD-CTX, 1.2 g/d×4 d) plus cyclosporine were offeved, which eventually led to a complete hematologic remission 12 months later. CONCLUSION: This was the first report of SAA associated with ß-thalassemia, and the regimen of HD-CTX led to a complete hematologic remission.