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1.
Eur J Neurol ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32166880

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS)-related genes and mutations have been increasingly discovered recently, and an improved understanding of genotype-phenotype relationships may help predict the disease course and refine genetic diagnosis. METHODS: We collected clinical data and blood samples from 268 patients and used next generation sequencing to comprehensively assay genetic variations in a panel of known ALS genes from 2015 to 2019. RESULTS: Among these patients, the mean age of onset was 52.30 ± 10.42 years with a mean diagnosis delay of 15.90 ± 11.88 months. Patients with SOD1, TARDBP, and FUS variants were more likely to suffer from familial ALS. Additionally, carriers of FUS variants displayed the earliest onset, followed by those with SOD1 variants. Patients with NEFH variants showed a closer link to pesticide exposure. Patients with SETX variants were prone to bulbar onset with moderate anxiety problems. No genotype-phenotype relations were found in SPG11 and ERBB4 mutants. CONCLUSION: Our findings uncovered some genotype-phenotype relationships and may help predict the disease course of ALS patients in southern China.

2.
Neurosci Lett ; 715: 134611, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31698026

RESUMO

Continuous theta burst stimulation (cTBS) has been widely recognized as a therapeutic treatment for ischemic stroke, but the underlying mechanism is still elusive. Here, we investigated the protective effects of cTBS in the posterior parietal cortex during the chronic phase of stroke in the photothrombotic ischemic model. Infarction volume and neuron excitability in the peri-infarct area were assessed using immunohistochemistry and whole-cell patch-clamp. Spatial cognitive function was measured using the Morris water maze. Gamma-Amino butyric acid (GABA) interneurons were responsive to cTBS, and cTBS induced elevated phasic inhibition rather than tonic inhibition. Given that GABA-A-mediated phasic inhibition was elevated during the chronic phase of ischemic stroke for 30 days and was beneficial for stroke recovery, we investigated the therapeutic potential of cTBS in promoting functional recovery and found that the elevated phasic inhibition by cTBS improved spatial cognitive function in the photothrombotic stroke mouse model with induction in the posterior parietal cortex. Our study indicates the mechanism by which cTBS may modify the excitability of the brain cortex and provides novel insight into the potential of cTBS to protect against neuronal dysfunction in ischemic stroke.

3.
Stem Cells ; 38(2): 218-230, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31648394

RESUMO

Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene that results in the production of neurotoxic mutant HTT (mHTT) protein. Suppressing HTT production with antisense oligonucleotides (ASOs) is a promising treatment strategy for HD; however, the difficulty of delivering ASOs to deep brain structures is a major barrier for its clinical application. The glymphatic system of astrocytes involving aquaporin 4 (AQP-4) controls the entry of macromolecules from the cerebrospinal fluid into the brain. Mesenchymal stem cells (MSCs) target astrocytes to inhibit neuroinflammation. Here we examined the glymphatic distribution of ASO in the brain and the therapeutic potential of combining intravenously injection of mesenchymal stem cells (IV-MSC) and ASOs for the treatment of HD. Our results show that Cy3-labeled ASOs entered the brain parenchyma via the perivascular space following cisternal injection, but the brain distribution was significantly lower in AQP-4-/- as compared with wild-type mice. Downregulation of the AQP-4 M23 isoform was accompanied by decreased brain levels of ASOs in BACHD mice as well as an increase in astrogliosis and phosphorylation of nuclear factor κB (NF-κB) p65. IV-MSC treatment restored AQP-4 M23 expression, attenuated astrogliosis, and decreased NF-κB p65 phosphorylation; it also increased the brain distribution of ASOs and enhanced the suppression of mHTT in BACHD mice. These results suggest that modulating glymphatic activity using IV-MSC is a novel strategy for improving the potency of ASO in the treatment of HD.

4.
Brain Res ; 1726: 146488, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586625

RESUMO

Acute ischemic stroke is a leading cause of disability with limited therapeutic options. Continuous theta burst stimulation (cTBS) has recently been shown to be a promising noninvasive therapeutic strategy for neuroprotection in ischemic stroke patients. Here, we investigated the protective effects of cTBS following acute infarction using a photothrombotic stroke (PTS) model in the right posterior parietal cortex (PPC) of C57BL/6 mice. Treatment with cTBS resulted in a reduction in the volume of the infarct region and significantly increased vascular diameter and blood flow velocity in peri-infarct region, as well as decreased the numbers of calcium binding adapter molecule 1 (Iba-1)-positive microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes. Moreover, the number of CD16/32 positive microglia was decreased, whereas the number of CD206 positive microglia was increased. In addition, performance in a water maze task was significantly improved. These results indicated that cTBS protected against PPC infarct region, leading to an improvement in spatial cognitive function, possibly as a result of changes to cerebral microvascular function and inflammatory responses.

5.
Lancet Oncol ; 21(2): 306-316, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31879220

RESUMO

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.

6.
Hum Mol Genet ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31813996

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disease with a heterogeneous etiology that involves both genetic and stress insults. Current LRRK2 PD animal models are only partly reproducing the characteristics of the disease with no or very subtle dopaminergic neuron degeneration. We developed a new model of PD that combines a sub-toxic MPTP insult to the G2019S-LRRK2 mutation. Our newly generated mice, overexpressing mutant G2019S-LRRK2 protein in the brain, displayed a mild, age-dependent progressive motor impairment, but no reduction of lifespan. Cortical neurons from G2019S-LRRK2 mice showed an increased vulnerability to various stress insults compared to neurons overexpressing wild type WT-LRRK2, or non-transgenic neurons. The exposure of LRRK2 transgenic mice to a subtoxic dose of MPTP resulted in severe motor impairment, selective loss of dopamine neurons and increased astrocyte activation, whereas non- transgenic mice with MPTP exposure showed no deficits. Interestingly, mice overexpressing WT-LRRK2 showed a significant impairment that was milder than for the mutant G2019S-LRRK2 mice. L-DOPA treatments could partially improve the movement impairments, but did not protect the dopamine neuron loss. In contrast, treatments with a LRRK2 kinase inhibitor, significantly reduced the dopaminergic neuron degeneration in the gene mutation and MPTP interaction model. Our studies provide a novel LRRK2 gene-MPTP interaction PD mouse model, which may reflect a more natural progression of LRRK-linked PD. This model provides a useful tool for future studies of PD pathogenesis and therapeutic intervention.

7.
BMC Complement Altern Med ; 19(1): 313, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730453

RESUMO

BACKGROUND: Jianpi-yangwei (JPYW), a traditional Chinese medicine (TCM), helps to nourish the stomach and spleen and is primarily used to treat functional declines related to aging. This study aimed to explore the antiaging effects and mechanism of JPYW by employing a Caenorhabditis elegans model. METHODS: Wild-type C. elegans N2 worms were cultured in growth medium with or without JPYW, and lifespan analysis, oxidative and heat stress resistance assays, and other aging-related assays were performed. The effects of JPYW on the levels of superoxide dismutase (SOD) and the expression of specific genes were examined to explore the underlying mechanism of JPYW. RESULTS: Compared to control worms, JPYW-treated wild-type worms showed increased survival times under both normal and stress conditions (P < 0.05). JPYW-treated worms also exhibited enhanced reproduction, movement and growth and decreased intestinal lipofuscin accumulation compared to controls (P < 0.05). Furthermore, increased activity of SOD, downregulated expression levels of the proaging gene clk-2 and upregulated expression levels of the antiaging genes daf-16, skn-1, and sir-2.1 were observed in the JPYW group compared to the control group. CONCLUSION: Our findings suggest that JPYW extends the lifespan of C. elegans and exerts antiaging effects by increasing the activity of an antioxidant enzyme (SOD) and by regulating the expression of aging-related genes. This study not only indicates that this Chinese compound exerts antiaging effects by activating and repressing target genes but also provides a proven methodology for studying the biological mechanisms of TCMs.


Assuntos
Envelhecimento/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Envelhecimento/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Humanos , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
9.
Ying Yong Sheng Tai Xue Bao ; 30(8): 2803-2812, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418206

RESUMO

Under the background of domestic and international pressure of carbon emission reduction and the requirement of energy structure adjustment, renewable energy development is under great pressure in China. Renewable energy development on abandoned mine areas has great potential due to its large area. It has great significance to develop renewable energy on abandoned mine areas for China's energy strategy. This study proposed the development scenarios of biomass energy and solar energy and estimated the development potential of renewable energy on abandoned mine areas in Liaoning Province. The results showed that the area of abandoned mine areas in Liaoning Pro-vince is 1227.6 km2, the potential of renewable energy development is large, and the potential of renewable energy in each scenario is quite different. In scenario 1, with the goal mode of maximizing the generation of photovoltaic power, the total generating capacity is 79.4 TWh, the total coal discount is 32.1 Mt standard coal, and the carbon reduction is 79.1 Mt CO2. In scenario 2, with the goal mode of maximizing biomass energy utilization, the total power generation from photovoltaic and biomass energy is 31.2-33.1 TWh, the total coal discount is 12.7-13.4 Mt standard coal, and the carbon emission reduction is 31.1-33.0 Mt CO2. In scenario 3, with the goal mode of maximizing comprehensive utilization of mine energy and consideration of ecological restoration, the total gene-rating capacity from photovoltaic and biomass energy is 62.3-63.7 TWh, the total coal discount is 25.1-25.7 Mt standard coal, and the carbon emission reduction is 62.1-63.5 Mt CO2. Under the three scenarios, the generation capacity range of is 31.2-79.4 TWh, accounting for 15.3%-38.9% of the total power consumption in Liaoning Province in 2016, which could be converted into 12.7-32.1 Mt standard coal, and contribute to a reduction of 31.1-79.1 Mt CO2 emission. The calculations of new energy development potential on abandoned mine areas and quantification of its capacity of alternatives to fossil energy will be helpful for carbon emission reduction, energy structure adjustment, and the recovery of the mining ecosystem.


Assuntos
Carvão Mineral , Mineração , Energia Renovável , Carbono , China
10.
Biogerontology ; 20(5): 665-676, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31332584

RESUMO

Liangyi Gao (LYG), a traditional Chinese medicine, is composed of Ginseng and Radix Rehmanniae Preparata, both of which have been shown to have antiaging properties. In Eastern countries, LYG is used to delay functional declines related to aging and has an obvious antiaging effect in clinical practice. However, little data from evidence-based medicine is available regarding whether LYG is beneficial overall, particularly with respect to lifespan, and how LYG functions. To address these issues, Caenorhabditis elegans, a useful organism for such studies, was employed to explore the antiaging effect and mechanism of LYG in this study. The results showed that LYG could obviously extend lifespan and slow aging-related declines in N2 wild-type C. elegans. To further characterize these antiaging effects and stress resistance, reproductive tests and other aging-related tests were performed. We found that LYG enhanced resistance against oxidative and thermal stress, reproduction, pharynx pumping, motility and growth in N2 wild-type C. elegans. In addition, we analyzed the mechanism for these effects by measuring the activity of superoxide dismutase (SOD) and the expression levels of aging-related genes. We found that LYG enhanced the activities of antioxidant enzymes and upregulated the genes daf-16, sod-3 and sir-2.1, which mediated stress resistance and longevity. In conclusion, LYG had robust and reproducible life-prolonging and antiaging benefits in C. elegans via DAF-16/FOXO regulation.

11.
J Cereb Blood Flow Metab ; : 271678X19856226, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31216943

RESUMO

Using a photothrombotic mouse model of single stroke, we show that a single stroke onset increases the nuclear factor-κB (NF-κB), NLR family CARD domain containing protein 4 (NLRC4), and absent in melanoma 2 (AIM2) inflammasomes, as well as the mRNA levels of NLRP3. Next, using a photothrombotic mouse model of recurrent stroke, we found that recurrent strokes increased the activation of NLRP3, exacerbated the brain damage and the pro-inflammatory response in wild type (WT) mice, but not in NLRP3 knockout (NLRP3 KO) mice. Additionally, we found that apoptosis-associated speck-like protein containing a CARD (ASC) protein level surrounding the infarct area was comparatively increased, but that ASC specks outside of microglia in both the ipsilateral and contralateral of stroke site were decreased in NLRP3 KO mice relative to wild-type (WT) controls, and the number of ASC specks surrounding the second infarct area was positively correlated to the damage scores. Mechanistically, we found that recombinant ASC (RecASC) activated NLRP3 and induced pro-inflammatory responses, exacerbating the outcome of ischemic stroke, in WT mice, but not in NLRP3 KO mice. We therefore conclude that the NLRP3 inflammasome is activated by two attacks of stroke, which act together with ASC to exacerbate recurrent strokes.

12.
J Neural Transm (Vienna) ; 126(8): 1029-1036, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154512

RESUMO

Objective measurement of walking speed and gait deficits are an important clinical tool in chronic illness management. We previously reported in Parkinson's disease that different types of gait tests can now be implemented and administered in the clinic or at home using Ambulosono smartphone-sensor technology, whereby movement sensing protocols can be standardized under voice instruction. However, a common challenge that remains for such wearable sensor systems is how meaningful data can be extracted from seemingly "noisy" raw sensor data, and do so with a high level of accuracy and efficiency. Here, we describe a novel pattern recognition algorithm for the automated detection of gait-cycle breakdown and freezing episodes. Ambulosono-gait-cycle-breakdown-and-freezing-detection (Free-D) integrates a nonlinear m-dimensional phase-space data extraction method with machine learning and Monte Carlo analysis for model building and pattern generalization. We first trained Free-D using a small number of data samples obtained from thirty participants during freezing of gait tests. We then tested the accuracy of Free-D via Monte Carlo cross-validation. We found Free-D to be remarkably effective at detecting gait-cycle breakdown, with mode error rates of 0% and mean error rates < 5%. We also demonstrate the utility of Free-D by applying it to continuous holdout traces not used for either training or testing, and found it was able to identify gait-cycle breakdown and freezing events of varying duration. These results suggest that advanced artificial intelligence and automation tools can be developed to enhance the quality, efficiency, and the expansion of wearable sensor data processing capabilities to meet market and industry demand.

13.
Brain Behav Immun ; 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31247290

RESUMO

Alcoholism is a risk factor for the development of cognitive decline and dementia. Here we demonstrated that the glymphatic function in the brain was impaired by alcohol administration. Acute moderate alcohol administration substantially retarded and reduced the entry of subarachnoid cerebrospinal fluid (CSF) via the paravascular space into the cerebral parenchyma, thus impaired CSF-interstitial fluid (ISF) exchange and parenchymal amyloid ß (Aß) peptide clearance. The elevated release of ß-endorphin and reduced cerebrovascular pulsatility after acute alcohol administration may account for the impairment of the glymphatic function. Chronic moderate alcohol consumption led to pronounced activation of astrocytes and a widespread loss of perivascular AQP4 polarization in the brain, which results in an irreversible impairment of the glymphatic function. The results of the study suggest that impaired glymphatic functions and reduced parenchymal Aß clearance found in both acute and chronic alcohol treatment may contribute to the development of cognitive decline and dementia in alcoholism.

14.
Clin Nucl Med ; 44(9): 707-713, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31205154

RESUMO

OBJECTIVE: Nonmotor symptoms (NMS) are critical players in the patients' quality of life in Parkinson disease (PD). Vesicular monoamine transporter type 2 (VMAT2) has been reported owing to a role in affecting dopamine neurons in the striatum. Therefore, this study set out to characterize the relationship between VMAT2 distribution in the striatum in relation to the NMS in PD. METHODS: Totally, 21 age-matched normal controls and 37 patients with PD in the moderate stages were included, followed by examination using F-DTBZ (F-AV133) PET/CT. The specific uptake ratio (SUR) of each striatal subregion was then determined with the occipital cortex as the reference background region. The overall NMSs of each individual patient were evaluated. Finally, the role of the striatal SURs in the clinical symptom scores were evaluated through the application of a Spearman correlation analysis as well as a multivariable stepwise regression analysis. RESULTS: Patients with PD, particularly those at a more advanced stage, exhibited a more pronounced reduction in SURs in the bilateral putamen and caudate nucleus (P < 0.05, vs healthy controls). Meanwhile, patients at more advanced PD stages were found to have significantly worse scores in NMS except cognitive function. The Spearman correlation analysis demonstrated that NMS scores, with the exception of cognition scores, were correlated with striatal SURs (P < 0.05). CONCLUSION: The key findings of the study identified a correlation between decreased striatal VMAT2 with a broad spectrum of NMS in patients with PD, highlighting the association between diminished dopamine supply and the development of NMS in PD.


Assuntos
Neostriado/metabolismo , Doença de Parkinson/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Qualidade de Vida
15.
Neuroreport ; 30(6): 428-433, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30829959

RESUMO

Ischemic stroke is a common life-threatening disease. Epidemiological studies have shown that chronic periodontitis is closely related to ischemic stroke. However, it remains unknown whether periodontitis plays a direct role in the injury of cerebral ischemia. To explore the role of chronic periodontitis in the development process of ischemic stroke, we combined two mouse models: experimental periodontitis induced by a periodontal injection of lipopolysaccharide and ischemic stroke induced by the photothrombotic method. Alveolar bone loss and inflammatory infiltration of the periodontal tissue were found in the mice with experimental periodontitis. Periodontitis significantly increased the infarction volume, and numbers of activated microglia and astrocytes. Furthermore, an increased expression of nod-like receptor protein 3 inflammasome and interleukin-1ß was detected in the peri-infarct region. We drew a conclusion that chronic periodontitis exacerbated ischemic stroke by increasing the activation of microglia/astrocytes and the expression of nod-like receptor protein 3 inflammasome and interleukin-1ß. This suggested that chronic periodontitis played a role in ischemic brain injury directly through exacerbating the inflammation of the damaged brain.


Assuntos
Infarto Cerebral/patologia , Inflamação/patologia , Periodontite/patologia , Animais , Infarto Cerebral/imunologia , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Periodontite/complicações , Periodontite/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia
16.
Drug Des Devel Ther ; 13: 173-182, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30643385

RESUMO

Purpose: Mild traumatic brain injury (mTBI), the most common type of TBI, can result in prolonged cognitive impairment, mood disorders, and behavioral problems. Reducing oxidative stress and inflammation can rescue the neurons from mTBI-induced cell death. Xyloketal B, a natural product from mangrove fungus, has shown good antioxidative and neuroprotective effects in several disease models. Here, we investigated the potential protection afforded by a xyloketal derivative, C53N, in a closed-skull mTBI model. Materials and methods: Skulls of mice were thinned to 20-30 µm thickness, following which they were subjected to a slight compression injury to induce mTBI. One hour after TBI, mice were intraperitoneally injected with C53N, which was solubilized in 0.5% dimethyl sulfoxide in saline. In vivo two-photon laser scanning microscopy was used to image cell death in injured parenchyma in each mouse over a 12-hour period (at 1, 3, 6, and 12 hours). Water content and oxidation index, together with pathological analysis of glial reactivity, were assessed at 24 hours to determine the effect of C53N on mTBI. Results: Cell death, oxidative stress, and glial reactivity increased in mTBI mice compared with sham-injured mice. Treatment with 40 or 100 mg/kg C53N 1 hour after mTBI significantly attenuated oxidative stress and glial reactivity and reduced parenchymal cell death at the acute phase after mTBI. Conclusion: The present study highlights the therapeutic potential of the xyloketal derivative C53N for pharmacological intervention in mTBI.


Assuntos
Lesões Encefálicas Traumáticas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Piranos/farmacologia , Animais , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glutationa/análise , Glutationa/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Piranos/administração & dosagem , Piranos/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo
17.
J Cereb Blood Flow Metab ; 39(9): 1776-1789, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29624118

RESUMO

Cerebral infarction causes secondary neurodegeneration and angiogenesis in thalamus, which impacts functional recovery after stroke. Here, we hypothesize that activation of ephrinB2 could stimulate angiogenesis and restore the secondary neurodegeneration in thalamus after cerebral infarction. Focal cerebral infarction was induced by middle cerebral artery occlusion (MCAO). Secondary damage, angiogenesis, amyloid-ß (Aß) deposits, levels of ephrinB2 and receptor for advanced glycation end product (RAGE) in the ipsilateral thalamus were determined by immunofluorescence and immunoblot. The contribution of ephrinB2 to angiogenesis was determined by siRNA-mediated knockdown of ephrinB2 and pharmacological activation of ephrinB2. The results showed that formation of new vessels and ephrinB2 expression was markedly increased in the ipsilateral thalamus at seven days after MCAO. EphrinB2 knockdown markedly suppressed angiogenesis coinciding with increased Aß accumulation, neuronal loss and gliosis in the ipsilateral thalamus. In contrast, clustered EphB2-Fc significantly enhanced angiogenesis, alleviated Aß accumulation and the secondary thalamic damage, which was accompanied by accelerated function recovery. Additionally, activation of ephrinB2 significantly reduced RAGE levels in the ipsilateral thalamus. Our findings suggest that activation of ephrinB2 promotes angiogenesis, ameliorates Aß accumulation and the secondary thalamic damage after cerebral infarction. Additionally, RAGE might be involved in Aß clearance by activating ephrinB2 in the thalamus.

18.
Neurobiol Aging ; 73: 230.e1-230.e4, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30293725

RESUMO

Genetic factors play significant roles in the causes of Parkinson's disease (PD). Recently, a meta-analysis of genome-wide association study (GWAS) has identified 17 loci associated with PD. The objective of our study was to investigate the association of 17 single-nucleotide polymorphisms with the risk of PD in Chinese population. We performed a case-control association study, and 1189 subjects comprising 652 PD patients and 537 controls were genotyped by using a Mass ARRAY System or a TaqMan assay. We found that rs601999 (OR (95% CI) = 3.378 (2.273-5.051), p < 0.001), rs11343 (OR (95% CI) = 0.426 (0.210-0.862), p = 0.018), rs353116 (OR (95% CI) = 0.738 (0.577-0.943), p = 0.015), and rs2280104 (OR (95% CI) = 1.371 (1.078-1.743), p = 0.010) were significantly associated with PD in Chinese population. However, no significant association was found in the remaining 13 single-nucleotide polymorphisms between both groups.


Assuntos
Estudos de Associação Genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Risco
19.
World J Pediatr ; 15(1): 66-71, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30443829

RESUMO

BACKGROUND: This study aimed to explore the value of applying a new pterin marker (isoxanthopterin) to the traditional urine pterin analysis to reduce the rate of mis-diagnosis of 6-pyruvoyltetrahydropterin synthase deficiency (PTPSD) and improve the accuracy of diagnosis. METHODS: We compared the urine neopterin (N), biopterin (B), isoxanthopterin (Iso), B% and Iso% levels between patients with phenylalanine hydroxylase deficiency and those with PTPSD, and found the most specific pterin biomarkers by ROC analysis. A positive cut-off value of urine pterins was determined. The effect of combined Iso% + B + B% in reducing PTPSD mis-diagnosis was evaluated, and the different urine pterin levels in PTPSD and false PTPSD (FPTPSD) were compared. The concordance of PTPSD diagnosis by the new pterin scheme and gene mutation analysis was determined. RESULTS: (1) Urinary B, B%, Iso and Iso% were significantly lower in PTPSD than those in phenylalanine hydroxylase-deficiency group (P < 0.01); (2) Iso%, B%, and B were the most specific markers; (3) The positive cut-off values of B, B%, Iso% for PTPSD were < 0.17 mmoL/moLCr, < 5.0%, and < 9.5%, respectively; (4) urinary B + B% + Iso% scheme significantly reduced the false-positive rate of PTPSD compared to traditional ones. The Iso% levels in FPTPSD group were higher than the ones in PTPSD group; (5) an accuracy of diagnosis for PTPSD was increased by 9-19% when Iso% was introduced to urinary pterin scheme. CONCLUSIONS: Iso% is helpful to reduce the rate of misdiagnosis of PTPSD in the diagnosis by urinary pterin analysis for hyperphenylalaninemias and improve the accuracy of diagnosis. This approach is worthy of further development and increased utilization.


Assuntos
Fenilcetonúrias/diagnóstico , Fósforo-Oxigênio Liases/deficiência , Xantopterina/urina , Biomarcadores/urina , Biopterina/urina , Cromatografia Líquida , Diagnóstico Diferencial , Erros de Diagnóstico/prevenção & controle , Humanos , Lactente , Neopterina/urina , Curva ROC
20.
Plant J ; 97(5): 887-900, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30466195

RESUMO

Dwarfing and semi-dwarfing are important agronomic traits that have great potential for the improvement of wheat yields. Rht12, a dominant gibberellic acid (GA)-responsive dwarfing gene from the gamma-ray-induced wheat mutant Karcagi 522M7K, is located in the long arm of chromosome 5A, which is closely linked with the locus Xwmc410. Rht12 is likely an ideal gene for GA biosynthesis and deactivation research in common wheat. However, information on the Rht12 locus and sequence is lacking. In this study, Rht12 significantly shortened stem cell length and decreased GA biosynthetic components. Using bulked segregant RNA-Seq, wheat 660k single nucleotide polymorphism chip detection, and newly developed simple sequence repeat markers, Rht12 was mapped to a 11.21-Mb region at the terminal end of chromosome 5AL, and was found to be closely linked with the Xw5ac207SSR marker with a 10.73-Mb fragment deletion in all of the homologous dwarfing plants. Transcriptome analyses of the remaining 483-kb region showed significantly higher expression of the TraesCS5A01G543100 gene encoding the GA metabolic enzyme GA 2-ß-dioxygenase in dwarfing plants than in high stalk plants, suggesting that Rht12 reduces plant height by activating TaGA2ox-A14. Taken together, our findings will promote cloning and functional studies of Rht12 in common wheat.

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