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1.
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.

2.
Immunology ; 157(3): 248-256, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31063220

RESUMO

Down-regulated chemerin expression has been reported to correlate with poor prognosis of several types of cancer including melanoma. All-trans retinoic acid (atRA) is a potent inducer of chemerin, and we previously reported that atRA inhibited murine melanoma growth through enhancement of anti-tumor T-cell immunity. Here, we aimed to investigate whether loss of endogenous chemerin accelerated melanoma growth and whether chemerin was involved in the melanoma-inhibitory effect of atRA. We demonstrated that chemerin was constitutively expressed in the skin, which was down-regulated during murine melanoma growth. Rarres2-/- mice, which are deficient in chemerin, exhibited aggravated tumor growth and impaired tumor-infiltrating natural killer (NK) cells that express CMKLR1, the functional receptor of chemerin. Topical treatment with atRA up-regulated skin chemerin expression, which was primarily derived from dermal cells. Moreover, atRA treatment significantly enhanced tumor-infiltrating NK cells, which was completely abrogated in Rarres2-/- mice and Cmklr1-/- mice, suggesting a dependency of NK cell recruitment on the chemerin-CMKLR1 axis in melanoma. Despite comparable melanoma growth detected in wild-type mice and Cmklr1-/- mice, lack of CMKLR1 partially abrogated the melanoma-inhibitory effect of atRA. This may be due to the inability to enhance tumor-infiltrating NK cells in Cmklr1-/- mice following atRA treatment. Collectively, our study suggests that down-regulation of chemerin could be a strategy used by cancers such as melanoma to impair anti-tumor NK cell immunity and identifies a new anti-tumor mechanism of atRA by up-regulating chemerin to enhance CMKLR1-dependent NK cell recruitment.

3.
Neuroimage ; 189: 688-699, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711469

RESUMO

The efficacy of neurofeedback is a point of great controversy, because a certain proportion of users cannot properly regulate their brain activities and thereby fail to benefit from neurofeedback. To address the neurofeedback inefficacy problem, the present study is aimed to design and implement a new neurofeedback system that can more effectively and consistently regulate users' brain activities than the conventional way of training users to voluntarily regulate brain activities. The new neurofeedback system delivers external visual stimuli continuously at a specific alpha phase, which is real-time decoded from ongoing alpha wave, to regulate the alpha wave. Experimental results show that the proposed training-free externally-regulated neurofeedback (ER-NF) system can achieve consistent (effective in almost all sessions for almost all users), flexible (either increasing or decreasing peak alpha frequency and alpha power), and immediate (taking or losing effect immediately after stimulation is on or off) modulation effects on alpha wave. Therefore, the ER-NF system holds great potential to be able to more reliably and flexibly modulate cognition and behavior.

4.
Postgrad Med J ; 95(1119): 46-47, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30696707

RESUMO

China has the largest stroke population and at-risk population in the world. However, it has a lower thrombolytic therapy rate and longer onset-to-needle time/door-to-needle time for patients who had an acute stroke compared with developed countries, which might be due to redundant procedures or inefficient systems. Things are changing due to some new initiatives. Two years ago, a new emergency system in China, Stroke Emergency Map, was first launched as a regional emergency system in Shenzhen, the bustling metropolis just north of Hong Kong. As a result of the Stroke Emergency Map in Shenzhen, the number of thrombolytic cases increased in the last 2 years, from 568 to 809 annually. The Stroke Emergency Map, first pioneered in Shenzhen and now spreading to the rest of China, is a comprehensive and interdisciplinary system. The benefits are not just the immediate improvements in the acute stroke care because the continuous data collection and audit allows for improvements in logistics and future strategies.


Assuntos
Fibrinolíticos/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/métodos , China/epidemiologia , Acesso aos Serviços de Saúde , Humanos , Acidente Vascular Cerebral/epidemiologia , Tempo para o Tratamento
5.
BMC Oral Health ; 18(1): 224, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30572852

RESUMO

BACKGROUND: The purpose of this study was to investigate the status of caries in deciduous teeth and the effect of diet and lifestyle habits on dental caries among 3- to 5-year-old preschool children in Jiangxi Province, China. METHODS: In total, 2880 cases involving preschool children were selected by stratified cluster sampling. The dental examination methods and criteria followed the WHO guidelines. SPSS 19.0 was used for the statistical analysis. Chi square tests were used to compare the caries prevalence among children with different social characteristics. Non-parametric tests were used to compare the decayed, missing and filled teeth (dmft) index values. Univariate and multivariate regression analyses were used to study the effect of diet and lifestyle habits on dental caries. RESULTS: The caries prevalence among the 2880 cases of 3- to 5-year-old preschool children in Jiangxi Province, China was 49.13%. There was no gender difference in this rate (P > 0.05). The caries prevalence increased with age (P < 0.05). The prevalence of caries in the rural areas was higher than that in the urban areas (P < 0.05). The deciduous central incisors and deciduous molars had a higher caries prevalence than the other deciduous teeth. According to the multivariate logistic regression analysis, the caries risk increased with living in a rural area, exclusive breastfeeding, greater frequency of daily snacking, high frequency of snacking before sleep and beginning to brush teeth at a late age; the caries risk decreased when parents helped their children brush their teeth. CONCLUSION: The caries prevalence among 3- to 5-year-old preschool children in Jiangxi was lower than the level throughout the country and lower than the rate in other developing countries. The children's diet and lifestyle habits were closely related to dental caries. Parents and children should be more aware of oral health, and parents should help their children develop healthy lifestyle behaviours.

6.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 36(6): 650-655, 2018 12 01.
Artigo em Chinês | MEDLINE | ID: mdl-30593112

RESUMO

OBJECTIVE: This study aimed to investigate the oral health service needs and dental treatment among 3-year-old to 5-year-old preschool children in Jiangxi province and provide data to support the development of relevant oral health policies, enhance the oral health service utilization and visit rate, and optimize oral manpower and service resources. METHODS: A total of 2 880 preschool children were selected via stratified cluster sampling. Dental examination methods and criteria according to the fourth national oral health epidemiological survey were adopted. Excel 2007 and SPSS 19.0 softwares were used for statistics analysis. Chi-square test and logistic regression analysis were performed. RESULTS: The caries prevalence was 49.13% (1 415/2 880) among the 2 880 cases of 3-
year-old to 5-year-old preschool children in Jiangxi province, approximately 53.37% (1 537/2 880) of which possessed oral health service needs. The parents of younger children assessed the oral situation better in older age than in their younger years (P<0.05), which was better in urban children than in rural children (P<0.05). The visiting rate of all the respondents was 12.33% (355/2 880), while the visiting rate of children with oral diseases was 17.31% (266/1 537). The top three reasons why patients did not visit the dentist were as follows: children's teeth have no problem, the teeth damage in teeth was considerably minimal, and primary teeth would be replaced without the need for treatment. The influencing factors included lower visiting rate in females than in males (OR=0.499, 95%CI: 0.411-0.606) and lower visiting rates in rural areas than in urban areas (OR=0.428, 95%CI: 0.353-0.519). Subjects with poor oral health and high oral knowledge scores possessed high dental service visit rates. CONCLUSIONS: The prevalence of caries in 3-year-old to 5-year-old preschool children in Jiangxi province is at a lower level than that in the national level. The proportion of the population actively seeking medical services is low, and their main purpose of treatment is to treat rather than prevention. Oral health education should be strengthened, and it should be incorporated to the contents of the kindergarten teacher training program to improve residents' awareness regarding children's oral health.


Assuntos
Saúde Bucal , Pré-Escolar , Índice CPO , Cárie Dentária , Feminino , Educação em Saúde Bucal , Humanos , Masculino , Prevalência , Dente Decíduo
7.
Front Neurosci ; 12: 782, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464741

RESUMO

Mutations in leucine-rich repeat kinase 2 (LRRK2) are common causes of familial Parkinson's disease (PD). Oxidative stress plays a key role in the pathogenesis of PD. Mutations in LRRK2 have been shown to increase susceptibility to oxidative stress. To explore mechanisms underlying susceptibility to oxidative stress in LRRK2 mutants, we generated stable Caenorhabditis elegans (C. elegans) strains in which human LRRK2 proteins including wild type LRRK2 (WT), G2019S LRRK2 (G2019S), and G2019S-D1994A kinase-dead LRRK2 (KD) were expressed in all neurons. Human 14-3-3 ß was injected into LRRK2 transgenic worms to allow co-expression of 14-3-3 ß and LRRK2 proteins. We found that G2019S transgenic worms had increased sensitivity to stress (heat and juglone treatment) and impaired stress-induced nuclear translocation of DAF-16. In addition, G2019S inhibited ftt2 (a 14-3-3 gene homolog in C. elegans) knockdown-associated nuclear translocation of DAF-16. Comparably, overexpression of human 14-3-3 ß could attenuate G2019S-associated toxicity in response to stress and rescued G2019S-mediated inhibition of sod-3 and dod-3 expression. Taken together, our study provides evidence suggesting that 14-3-3-associated inhibition of DAF-16 nuclear translocation could be a mechanism for G2019S LRRK2-induced oxidative stress and cellular toxicity. Our findings may give a hint that the potential of 14-3-3 proteins as neuroprotective targets in PD patients carrying LRRK2 mutations.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30232887

RESUMO

Seeking for ultrasensitive and low-cost substrates is highly demandable for practical applications of surface-enhanced Raman scattering (SERS) technology. In this work, we report an ultrasensitive SERS-active substrate based on wet-chemistry-synthesized vertically aligned large-area TiO2 nanosheets (NSs) decorated by densely packed gold nanoparticles (Au NPs) with sub-5 nm gaps. Via a multistep successive deposition process, three-dimensional-stacked Au NPs sandwiched by a 3 nm SiO2 layer were assembled onto the TiO2 NS, enabling numerous hotspots due to the formation of both ultratiny plasmonic gaps and semiconductor/metal interfaces. Experimental results show that the fabricated substrate displays a detection limit down to 10 fM (10-14 M) without involving any condensation process by using the crystal violet as probe molecules. Control experiments and electromagnetic simulations indicate that the nanogaps defined by the 3 nm spacer are essential for the obtained excellent SERS performance. With its ultrasensitive detection capability, we demonstrate that the fabricated SERS substrate can be used for the trace analysis of melamine in milk.

9.
Eur J Med Chem ; 148: 63-72, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29454917

RESUMO

Ageing is a complex but universal phenomenon that progressively challenges the homeostasis network and finally leads to the dysfunction of organisms and even death. Previous studies demonstrated that xyloketal B and its derivatives, a series of marine novel ketone compounds, possessed unique antioxidative effects on endothelial and neuronal oxidative injuries. In this study, we examined the effects of xyloketal derivatives on extending lifespan and healthspan of Caenorhabditis elegans. The results showed that most selected xyloketals could protect Caenorhabditis elegans against heat stress and extend the lifespan of worms. Compound 15, a benzo-1, 3-oxazine xyloketal derivative, possessed most potent effect in anti-heat stress assay and significantly attenuated ageing-related decrease of pumping and bending of the worms in healthspan assay. In addition, the beneficial effect of 15 was abolished in PS3551 worms, a strain that possesses non-functional heat shock transcription factor-1 (HSF-1). Furthermore, 15 increased the expression of heat shock protein 70 (HSP70), a downstream molecular chaperone of HSF-1. These results indicated that HSF-1 might contribute to the protective effect of this compound in Caenorhabditis elegans ageing. Molecular docking studies suggested that these xyloketal derivatives were bound to the DNA binding domain of HSF-1, promoted the conformation of HSF-1, thus strengthened the interaction between the HSF-1 and related DNA. ALA-67, ASN-74 and LYS-80 of binding region might be the key amino residues during the interaction. Finally, compound 15 could reduce the paralysis of the CL4176 worms, a transgenic strain expressing human Aß3-42 under a temperature-inducible system. Collectively, these data indicate that xyloketals have potential implications for further evaluation in anti-ageing studies.


Assuntos
Envelhecimento/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Piranos/química , Estresse Fisiológico/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Animais , Animais Geneticamente Modificados , Sítios de Ligação , Caenorhabditis elegans/fisiologia , DNA/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Longevidade/efeitos dos fármacos , Simulação de Acoplamento Molecular , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Ligação Proteica , Piranos/farmacologia
10.
Mol Med Rep ; 16(1): 254-262, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28487947

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disorder that affects ~2% of the human population aged >65. α­synuclein serves a role in the pathogenesis of PD as it is a primary component of Lewy bodies, a pathological feature of PD. Endosomal­lysosomal dysfunction may be a key factor involved in the pathophysiology of PD, and may cause PD­associated neurodegeneration via α­synuclein­dependent and ­independent mechanisms. The D620N mutation in the endosomal­lysosomal gene, vacuolar protein sorting­associated protein 35 (VPS35), has been linked to PD. To clarify the underlying cellular mechanism of the VPS35 D620N mutation in PD, cell growth and endosomal­lysosomal functions were investigated in Saccharomyces cerevisiae (sc) yeast cells that exhibited various expression levels of scVPS35, in the presence or absence of non­toxic expression levels of α­synuclein. Overexpression of the scVPS35 D686N mutation (the yeast equivalent of D620N) did not lead to toxicity in yeast. However, the co­expression of high copy numbers of scVPS35 D686N and low copy numbers of α­synuclein caused toxicity, whereas the co­expression of scVPS35 wild­type and α­synuclein did not. In addition, the scVPS35 D686N mutant enhanced α­synuclein aggregation. Fragmentation of vacuoles and subsequent inhibition of lysosome function was evident in yeast cells bearing the scVPS35 mutant. The results of the present study suggested that α­synuclein and scVPS35 were interlinked via the endosomal­lysosome pathway, which is important for the pathogenesis of PD.


Assuntos
Viabilidade Microbiana/genética , Mutação , Doença de Parkinson/genética , Proteínas de Transporte Vesicular/genética , Leveduras/genética , Leveduras/metabolismo , alfa-Sinucleína/metabolismo , Humanos , Lisossomos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregados Proteicos , Agregação Patológica de Proteínas , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte Vesicular/metabolismo
11.
Drug Des Devel Ther ; 10: 1443-51, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27110099

RESUMO

Huntington's disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt). Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington's disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases. To identify potential neuroprotective molecules for Huntington's disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington's disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a stable trimeric complex that can prevent the formation of mutant Htt aggregates. Taken together, we conclude that xyloketal derivatives could be novel drug candidates for treating Huntington's disease. Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds. Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.


Assuntos
Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Fármacos Neuroprotetores/farmacologia , Agregados Proteicos/efeitos dos fármacos , Piranos/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Caenorhabditis elegans/genética , Proteína Huntingtina/química , Proteína Huntingtina/genética , Doença de Huntington/tratamento farmacológico , Doença de Huntington/prevenção & controle , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Agregados Proteicos/genética , Piranos/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
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