RESUMO
Background: Urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) is a biomarker for the early diagnosis of Alzheimer's disease (AD). It remains unclear whether hepatorenal function affects the urinary AD7c-NTP level. Objective: To evaluate the effects of hepatorenal function on urinary AD7c-NTP level. Methods: We enrolled 453 participants aged 60-100 years. An automated chemistry analyzer was used to determine the indicators of serum hepatorenal function. Enzyme-linked immunosorbent assay was used to measure the urinary AD7c-NTP level. Results: Spearman's correlation analysis showed a negative correlation between urinary AD7c-NTP levels and indicators of hepatorenal function, including albumin (râ=â-0.181, pâ<â0.001), albumin/globulin ratio (râ=â-0.224, pâ<â0.001), cholinesterase (râ=â-0.094, pâ=â0.046), total carbon dioxide (râ=â-0.102, pâ=â0.030), and glomerular filtration rate (râ=â-0.260, pâ<â0.001), as well as a positive correlation with globulin (râ=â0.141, pâ=â0.003), aspartate transaminase (râ=â0.186, pâ<â0.001), blood urine nitrogen (râ=â0.210, pâ<â0.001), creatinine (râ=â0.202, pâ<â0.001), uric acid (râ=â0.229, pâ<â0.001), and cystatin C (râ=â0.265, pâ<â0.001). The least absolute shrinkage and selection operator (LASSO) regression analysis and multiple linear regression model analyses showed that the statistically significant hepatorenal indicators for predicting AD7c-NTP were A/G (pâ=â0.007), AST (pâ=â0.002), BUN (pâ=â0.019), and UA (pâ=â0.003). Conclusions: The effects of hepatorenal indicators should be considered when using urinary AD7c-NTP levels in clinical settings.
Assuntos
Doença de Alzheimer , Biomarcadores , Humanos , Feminino , Masculino , Idoso , Estudos Transversais , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Biomarcadores/urina , Biomarcadores/sangue , Doença de Alzheimer/urina , Doença de Alzheimer/diagnóstico , Cistatina C/sangue , Cistatina C/urina , China/epidemiologia , Proteínas do Tecido Nervoso/urina , Taxa de Filtração Glomerular/fisiologia , Povo Asiático , Rim/fisiopatologia , Testes de Função Hepática , População do Leste AsiáticoRESUMO
Clinical studies have shown that asthma is a risk factor for dementia or Alzheimer's disease (AD). To investigate whether asthma aggravates AD in APP/PS1 mice and explore the potential mechanisms, an asthma model was established using six-month-old APP/PS1 mice, and montelukast was used as a therapeutic agent in APP/PS1 mice with asthma. The Morris water maze test showed that asthma aggravates spatial learning and memory abilities. Asthma also upregulates the NF-κB inflammatory pathway in APP/PS1 mice and promotes the expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid-ß (Aß) deposition, neuronal damage, synaptic plasticity deficiency, activation of microglia and astrocytes. The level of LTD4 and its receptor CysLT1R in the hippocampus of APP/PS1 mice after the asthma modeling was established was higher than that in APP/PS1 mice, suggesting that asthma may affect the pathology of AD through LTD4 and its receptor Cys-LT1R. Montelukast ameliorates these pathological changes and cognitive impairment. These results suggest that asthma aggravates AD pathology and cognitive impairment of APP/PS1 mice via upregulation of the NF-κB inflammatory pathway, and montelukast ameliorates these pathological changes.
Assuntos
Acetatos , Doença de Alzheimer , Disfunção Cognitiva , Ciclopropanos , Quinolinas , Sulfetos , Camundongos , Animais , Doença de Alzheimer/metabolismo , NF-kappa B/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/uso terapêutico , Leucotrieno D4/uso terapêutico , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Camundongos Transgênicos , Ácido Aspártico Endopeptidases/metabolismo , Ácido Aspártico Endopeptidases/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/metabolismo , Transdução de Sinais , Modelos Animais de Doenças , Presenilina-1/metabolismoRESUMO
Objective: Mitochondrial dysfunction is evident in the early stage of Alzheimer's disease (AD). Therefore development of drugs that protect mitochondrial function is a promising strategy for AD. The present work was to investigate the effects of 2, 3, 5, 4'-Tetrahydroxystilbene-2-O-ß-d-glucosides (TSG) on a mitochondrial dysfunction cell model induced by sodium azide and elucidate the underlying mechanisms. Methods: Mitochondrial membrane potential (MMP) was detected by a fluorescence method. Cellular adenosine triphosphate (ATP) level was measured using a firefly luciferase-based kit. Reactive oxygen species (ROS) was detected using dichlorofluorescin diacetate (DCFH-DA). The expression levels of Bcl-2 and Bax were measured by Western blotting assay. Flow cytometry was utilized to measure apoptosis. Results: Pretreatment of TSG (25-200 µmol/L) for 24 h significantly elevated MMP and ATP content, reduced ROS level and Bax/Bcl-2 ratio, and inhibited apoptosis in SH-SY5Y cells exposed to sodium azide. Conclusion: These results suggest that TSG protects SH-SY5Y cells against sodium azide-induced mitochondrial dysfunction and apoptosis. These findings are helpful to understand the protective effect of TSG on mitochondria, which are involved in the early stage of AD.
RESUMO
The roles of miRNAs in the development of cancer have made them promising tools for novel therapeutic approaches. However, the successful delivery of miRNAs to cancer cells has been hampered by difficulties in developing an effective and sustainable delivery mechanism. Exosomes are small endogenous membrane vesicles that mediate communication between cells by delivering genetic materials. Thus, given their intrinsic properties, exosomes have been a focus for use as biological delivery vehicles for miRNAs transfer. Whether exosomes can effectively deliver exogenous miRNAs to pancreatic ductal adenocarcinoma (PDAC) cells has not been thoroughly investigated. Here, we used exosomes from human umbilical cord mesenchymal stromal cells (hucMSCs) to deliver exogenous miR-145-5p, which inhibited PDAC cell proliferation and invasion and increased apoptosis and cell cycle arrest, concomitant with decreased Smad3 expression in vitro. Using a mouse model, we also demonstrated that overexpressing miR-145-5p significantly reduced the growth of xenograft tumors in vivo. Our findings provide novel insights that exosomes might be an attractive therapeutic vehicle for the clinical administration of miRNAs in patients with PDAC.
Assuntos
Carcinoma Ductal Pancreático/terapia , Exossomos/transplante , Células-Tronco Mesenquimais , MicroRNAs/metabolismo , Neoplasias Pancreáticas/terapia , Cordão Umbilical/citologia , Animais , Antígenos CD/metabolismo , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Caderinas/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Exossomos/genética , Exossomos/metabolismo , Exossomos/ultraestrutura , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteína Smad3/metabolismo , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Autologous neural stem cells (NSCs) may offer a promising source for deriving dopaminergic (DA) cells for treatment of Parkinson's disease (PD). Methods: By using Sendai virus, human peripheral blood mononuclear cells (PBMNCs) were reprogrammed to induced NSCs (iNSCs), which were then differentiated to dopaminergic neurons in vitro. Whole-genome deep sequencing was performed to search for mutations that had accumulated during the reprogramming and expansion processes. To find the optimal differentiation stage of cells for transplantation, DA precursors obtained at various differentiation time points were tested by engraftment into brains of naïve immunodeficient mice. At last, the safety and efficacy of iNSC-derived DA precursors were tested by transplantation into the striatum of immunodeficient PD mouse models. Results: PBMNC-derived iNSCs showed similar characteristics to fetal NSCs, and were able to specifically differentiate to DA neurons with high efficiency in vitro. The sequencing data proved that no harmful SNVs, Indels and CNVs were generated during the reprogramming and expansion processes. DA precursors obtained between differentiation day 10 to 13 in vitro were most suitable for transplantation when a balanced graft survival and maturation were taken into account. Two weeks after transplantation of DA precursors into mouse PD models, the motor functions of PD mice started to improve, and continued to improve until the end of the experiments. No graft overgrowth or tumor was observed, and a significant number of A9-specific midbrain DA neurons were surviving in the striatum. Conclusion: This study confirmed the efficacy of iNSC-derived DA precursors in a mouse PD model, and emphasized the necessity of genomic sequencing and vigorous safety assessment before any clinical translation using iNSCs.
Assuntos
Transplante de Células/métodos , Neurônios Dopaminérgicos/fisiologia , Células-Tronco Neurais/fisiologia , Doença de Parkinson/terapia , Animais , Células Sanguíneas , Diferenciação Celular , Técnicas de Reprogramação Celular , Modelos Animais de Doenças , Humanos , Locomoção , Camundongos , Doença de Parkinson/patologiaRESUMO
BACKGROUND: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a biomarker for Alzheimer's disease (AD). OBJECTIVE: The aim of the present study was to investigate the distribution of Alzheimer-associated neuronal thread protein and its relationship to common chronic diseases in the general population. METHODS: Urine samples of 1,805 participants were collected from four districts (Xi Cheng, Fang Shan, Tong Zhou, and Yan Qing) in Beijing. The assessment in this study included a questionnaire that captured participants' demographic information, use of medication and histories of disease, neurological examinations, psychometric evaluations, physical and clinical examinations, and laboratory tests. RESULTS: Urine AD7c-NTP level was increased among the population over 60 years old and females exhibited higher levels than males. These results controlled for other demographic factors such as education levels, employment status, body mass index and current residence. The urine AD7c-NTP levels exhibited no association with non-neurological diseases (0.3346±0.4482 ng/ml), such as hypertension (0.3445±0.4187), stroke (0.3652±0.4010), diabetes (0.3319±0.4371), dyslipidemia (0.3440±0.4314), renal insufficiency (0.3223±0.3909), cancer (0.5055±1.0006), chronic lung disease (0.2911±0.2852), chronic liver disease (0.5579±0.6726), severe depression symptoms (0.5186±0.7040), and mild depression symptoms (0.3669±0.3811). CONCLUSIONS: Cut-off values for urine AD7c-NTP levels for different age groups and genders should be established. AD7c-NTP levels proved relatively stable in the body and were not impacted by demographic factors or common chronic diseases.
Assuntos
Doença Crônica/epidemiologia , Proteínas do Tecido Nervoso/urina , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/urina , Biomarcadores/sangue , Biomarcadores/urina , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Fatores SocioeconômicosRESUMO
Lmx1a plays a central role in the specification of dopaminergic (DA) neurons, which potentially could be employed as a key factor for trans-differentiation to DA neurons. In our previous study, we have converted somatic cells directly into neural stem cell-like cells, namely induced neural stem cells (iNSCs), which further can be differentiated into subtypes of neurons and glia in vitro. In the present study, we continued to test whether these iNSCs have therapeutic effects when transplanted into a mouse model of Parkinson's disease (PD), especially when Lmx1a was introduced into these iNSCs under a Nestin enhancer. iNSCs that over-expressed Lmx1a (iNSC-Lmx1a) gave rise to an increased yield of dopaminergic neurons and secreted a higher level of dopamine in vitro. When transplanted into mouse models of PD, both groups of mice showed decreased ipsilateral rotations; yet mice that received iNSC-Lmx1a vs. iNSC-GFP exhibited better recovery. Although few iNSCs survived 11weeks after transplantation, the improved motor performance in iNSC-Lmx1a group did correlate with a greater tyrosine hydroxylase (TH) signal abundance in the lesioned area of striatum, suggesting that iNSCs may have worked through a non-autonomous manner to enhance the functions of remaining endogenous dopaminergic neurons in brain.
Assuntos
Proteínas com Homeodomínio LIM/metabolismo , Células-Tronco Neurais/transplante , Doença de Parkinson/terapia , Fatores de Transcrição/metabolismo , Animais , Comportamento Animal , Diferenciação Celular , Linhagem Celular , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Elementos Facilitadores Genéticos/genética , Proteínas com Homeodomínio LIM/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nestina/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Doença de Parkinson/patologia , Fatores de Transcrição/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Cysteamine is a degradation product of the amino acid cysteine and a reduced form of cystamine. Cysteamine exhibits strong antioxidant activity and has been implicated in the treatment of neurodegenerative disorders such as Huntington's disease. In the present study, we investigated whether cysteamine confers protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced toxicity in the dopaminergic neurons in a mouse model for Parkinson's disease (PD). The loss of dopaminergic (DA) neurons and reduction in striatal DA concentrations induced by MPTP was ameliorated to a significant extent by pretreatment with low (20mg/kg/day), but not high (75mg/kg/day), dose of cysteamine 4days prior to and subsequently along with the MPTP treatment. Consistently, the increased production of pro-oxidants, such as reactive oxygen species (ROS) and malondialdehyde (MDA), was significantly suppressed by low dose of cysteamine. Conversely, the reduction in GSH level caused by MPTP exposure was significantly attenuated by pretreatment of cysteamine. In addition, the inhibited secretion of the brain-derived neurotrophic factor (BDNF) by neurons derived from substantia nigra pars compact (SNpc) of MPTP-treated mice was significantly restored by cysteamine administration. Our results demonstrate that cysteamine at low dose confers potent neuroprotection against MPTP-induced toxicity of dopaminergic neurons, and may become a potential therapeutic strategy for PD.