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Background: Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer's disease continuum (ADC). Objective: This study focused on the associations between two single nucleotide polymorphisms (SNPs) (rs3793790 and rs2177370) located in the CHAT gene and donepezil response in ADC patients, and further evaluated the associations between the two SNPs and ADC. Material and Methods: According to 2018 National Institute on Aging and Alzheimer's Association (NIA-AA) standard, amyloid ß-protein positive (Aß+) and negative (Aß-) patients were recruited according to the Aß-PET/CT standard. rs3793790 and rs2177370 were genotyped in buccal swab samples by using the MassARRAY system. We used the Mini Mental State Examination (MMSE) in Chinese version, caregiver evaluation, and prescribing behavior to assess therapeutic response during the 9-month period. Using logistic regression models, we analyzed the relationship between the two SNPs and donepezil response in 58 Aß+ patients treated with donepezil alone at the initial diagnosis of ADC. We also explored a probable link between the two SNPs and ADC in 147 Aß+ and 73 Aß- patients using a logistic regression analysis. Results: The chance of donepezil response was higher in patients with the G allele of rs3793790 and/or the A allele of rs2177370 than in those without (odds ratio (OR) 6.83, 95% confidence interval (CI): 1.64-28.49). Additionally, the rs3793790 variant was not associated with ADC, whereas the A allele in rs2177370 increased 1.51-fold the ADC risk (OR 2.51, 95% CI: 1.28-4.95). Conclusion: The genetic variants of rs3793790 and rs2177370 were associated with the donepezil response, and rs2177370 may have a moderate relationship with the risk of ADC.
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Enfermedad de Alzheimer , Donepezilo , Polimorfismo de Nucleótido Simple , Humanos , Donepezilo/uso terapéutico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Femenino , Masculino , Anciano , Anciano de 80 o más Años , Genotipo , Modelos Logísticos , Inhibidores de la Colinesterasa/uso terapéutico , Pruebas de Estado Mental y DemenciaRESUMEN
Background: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. Objective: We summarized the current evidence from several aspects and further quantified these associations. Methods: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Results: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer's disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI)â=â1.21-1.65) and a 1.57-fold excess risk for AD (95% CIâ=â1.15-2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CIâ=â1.19-1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearityâ=â0.0000) and AD (pnonlinearityâ=â0.0042). The approximate 77.5-100ânmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1ânmol/L. Conclusions: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention.
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Disfunción Cognitiva , Demencia , Deficiencia de Vitamina D , Vitamina D , Humanos , Vitamina D/sangre , Disfunción Cognitiva/sangre , Disfunción Cognitiva/epidemiología , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/epidemiología , Demencia/epidemiología , Demencia/sangre , Estudios Prospectivos , Factores de Riesgo , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/epidemiologíaRESUMEN
Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.
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Enfermedad de Alzheimer , Fragmentos de Péptidos , Sustancia P/análogos & derivados , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Inteligencia Artificial , Estudio de Asociación del Genoma Completo , Simulación del Acoplamiento Molecular , Trastornos de la Memoria/metabolismoRESUMEN
The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer's disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.
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Enfermedad de Alzheimer , MicroARNs , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Astrocitos/metabolismo , Modelos Animales de Enfermedad , Ratones Transgénicos , MicroARNs/metabolismo , Neuronas/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , HumanosRESUMEN
PURPOSE: The oral microbiota is closely associated with systemic health, but few studies have investigated the oral microbiota in patients with obstructive sleep apnea (OSA). This study aimed to identify the variation of oral microbiota among patients with severe OSA, and the change of oral microbiota after treatment with continuous positive airway pressure (CPAP). METHODS: Participants were enrolled in the study from November 2020 to August 2021. Sleep parameters using full nocturnal polysomnography (PSG) were collected on healthy controls, patients with severe OSA, and patients with severe OSA after CPAP treatment for 3 months. Oral samples were also collected by rubbing disposable medical sterile swabs on the buccal mucosa. Routine blood tests and biochemical indicators were measured using the fully automated biochemical analyzer. Oral microbial composition of oral samples were determined using whole-genome metagenomic analysis in all participants. Correlations were analyzed between the oral microbiota and blood lipids. RESULTS: Study enrollment included 14 participants, 7 healthy controls and 7 patients with severe OSA. At the species level, the relative abundances of Prevotella, Alloprevotella, Bacteroides, Veillonella_tobetsuensis, Candidatus saccharimonas, and Leptotrichia in the groups with severe OSA were significantly lower than those in the healthy controls (P both < 0.05). The abundances of Capnocytophaga, Veillonella, Bacillus_anthracis, Eikenella, and Kingella were significantly higher whereas the abundances of Gordonia and Streptococcus were significantly lower in the group with severe OSA compared to the severe OSA-CPAP group (P < 0.05 for both). According to the Kyoto Encyclopedia of Genes and Genomes (KEGG), 4 pathways changed in the group with severe OSA compared with healthy controls (P both < 0.05). Pathways related to Novobiocin biosynthesis, 2-Oxocarboxylic acid metabolism, and Histidine metabolism were enriched in the patients with severe OSA. Nine pathways showed significant differences with regard to the relative abundances of phenylalanine metabolism; alanine, aspartate, and glutamate metabolism; one carbon pool by folate; monobactam biosynthesis; 2-oxocarboxylic acid metabolism; arginine biosynthesis and vitamin B6 metabolism; novobiocin biosynthesis; and arginine and proline metabolism, which were significantly higher in the group with severe OSA compared to the severe OSA-CPAP group (P both < 0.05). The Spearman correlation analysis between blood lipid parameters and oral microbiota components showed that negative correlations were observed between total cholesterol and Streptomyces (r = - 0.893, P = 0.007), and high-density lipoprotein cholesterol (HDL-C) and Gordonia (r = - 0.821, P = 0.023); positive correlations were observed between HDL-C and Candidatus saccharimonas (r = 0.929, P = 0.003), and low-density lipoprotein cholesterol (LDL-C) and Capnocytophaga (r = 0.893, P = 0.007). CONCLUSION: There was an apparent discrepancy of the oral microbiota and metabolic pathways between the group with severe OSA and controls, and CPAP significantly changed oral microbial abundance and metabolic pathways in patients with severe OSA. Correlation analysis showed that these oral bacteria were strongly correlated with the blood lipids level.
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Microbiota , Apnea Obstructiva del Sueño , Humanos , Novobiocina , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/terapia , LDL-Colesterol , Lípidos , Presión de las Vías Aéreas Positiva Contínua , Microbiota/genéticaRESUMEN
AIM: Angiogenesis plays a major role in atherosclerotic plaque development and instability. Our study aims to develop a novel optical and magnetic resonance (MR) dual-modality molecular imaging probe to early detect unstable plaques in vivo by targeting biomarkers of angiogenesis in murine models of atherosclerosis (AS). METHODS: Immunofluorescence and western blot were used to detect the expression of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in activated Human Umbilical Vein Endothelial Cells (HUVECs). After synthesis and identification of novel short peptide VRBP1-targeted VEGFR2, HUVECs were co-cultured with FITC-VRBP1 to test specific affinity of VRBP1. Then VRBP1-UCNPstargeting VEGFR2 were constructed by conjugating VRBP1 to the surface of NaGdF4:Yb,Er@NaGdF4 nanoparticles. The characterization of the nanoparticles was performed by transmission electron microscopy (TEM), distribution of size, hydrodynamic size, zeta potential, absorption spectra, emission spectra, imaging intensity of different concentrations, binding affinity and cytotoxicity of nanoprobes in vitro. The upconversion luminescence (UCL) and MR imaging were performed to identify unstable atherosclerotic plaque in ApoE-/- mice in vivo and ex vivo. Morphological staining was used to verify AS model and angiogenesis, and Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES) was used to confirm accumulation of the nanoparticles after imaging. RESULTS: After induced by hypoxia and ox-LDL, the expression of VEGFR2 in activated HUVECs was enhanced. FITC-VRBP1 can specifically bind to the HUVECs. Characterization of the nanoparticles showed that particles size is uniform with a stable structure, specific optical and MR signal, good binding affinity to VEGFR2 and low cytotoxicity. In vivo and ex vivo UCL imaging and quantitative analysis revealed that distinctive optical signal was observed in the regions of left carotid common arteries (LCCAs) of AS group after injection of VRBP1-UCNPs. Higher signal intensity on T1-weighted MR imaging appeared in the LCCA wall of AS group after injection. The results of morphological staining demonstrated angiogenesis in the atherosclerotic plaques, Gd ions in LCCAs, aortic arch and renal arteries bifurcations detected by ICP-AES confirmed accumulation of the nanoparticles in plaque. CONCLUSIONS: We successfully design and synthesize a novel UCNPs using peptide VRBP1 targeting to VEGFR2. In vivo imaging demonstrates that VRBP1-UCNPs can be used to perform optical/MR dual-modality imaging targeting angiogenesis in plaques, which is a promising technique to early detect unstable atherosclerosis.
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Aterosclerosis , Placa Aterosclerótica , Animales , Humanos , Ratones , Placa Aterosclerótica/diagnóstico por imagen , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Células Endoteliales/metabolismo , Fluoresceína-5-Isotiocianato , Factor A de Crecimiento Endotelial Vascular , Aterosclerosis/metabolismo , Neovascularización Patológica/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Apolipoproteínas ERESUMEN
BACKGROUND: Synaptic abnormalities in synaptic proteins are the initial hallmarks of Alzheimer's disease (AD). The higher level of palmitoylation of synaptic proteins was closely associated with amyloid-ß (Aß) in AD. Cattle encephalon glycoside and ignotin (CEGI) have been shown to act as multitarget neurotrophic agents in APPswe/PS1dE9 (APP/PS1) transgenic AD mice. However, it is not clear whether CEGI can influence Aß deposition or whether it does so by the regulation of protein palmitoylation and expression of synaptic proteins in transgenic AD mice. OBJECTIVE: In this study, we investigated the roles of CEGI in modulating postsynaptic density protein 95 (PSD-95) palmitoylation, Aß pathologies, and expression of synaptic-associated proteins in APP/PS1 mice. METHODS: Five-month-old APP/PS1 mice were treated intraperitoneally with 6.6âmL/kg of CEGI for 6 weeks. At the end of the treatment period, APP/PS1 mice were subjected to Morris water maze to test their cognitive functions. Acyl-biotinyl exchange (ABE) for PSD-95 palmitoylation, immunofluorescent staining for expression of PSD-95, N-methyl-D-aspartic acid receptor subunit 2B (NR2B), and synaptotagmin 1 (SYT1) were assessed in mouse brain sections. RESULTS: CEGI treatment in APP/PS1 mice significantly reduced Aß deposition, relieved memory deficits, and decreased PSD-95 palmitoylation while markedly increasing the expression of PSD-95, NR2B, and SYT1 in the frontal cortex. There was a significant correlation between Aß expression and PSD-95 palmitoylation in APP/PS1 mice. CONCLUSION: Our findings demonstrate that CEGI improved AD-like neuropathology, possibly by inhibiting PSD-95 palmitoylation, improving learning memory, and enhancing expression of synaptic-associated proteins, representing a potential therapy for AD treatment.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/patología , Bovinos , Modelos Animales de Enfermedad , Homólogo 4 de la Proteína Discs Large/metabolismo , Lóbulo Frontal/patología , Glicósidos , Lipoilación , Ratones , Ratones Transgénicos , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Atherosclerosis-related cardiovascular diseases are the leading cause of mortality worldwide. Macrophage-derived foam cell formation is a critical early event in atherogenesis. However, the molecular pathways involved in this disease have not been fully elucidated. Interleukin (IL)-36 plays a crucial role in inflammation, and this study was conducted to investigate the possible role of IL-36γ in the pathogenesis and regulation of atherosclerosis. In this study, we show that IL-36γ regulates inflammatory responses and lipoprotein metabolic processes in macrophages and exerts its atherosclerosis-promoting effects by increasing macrophage foam cell formation and uptake of oxidized low-density lipoproteins. Mechanistically, IL-36γ specifically upregulates expression of the scavenger receptor CD36 through the phosphoinositide 3-kinase pathway in macrophages. These results contribute to our understanding of IL-36γ as a novel regulator of foam cell formation and atherogenesis progression.
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Aterosclerosis/metabolismo , Aterosclerosis/patología , Progresión de la Enfermedad , Células Espumosas/metabolismo , Interleucina-1/metabolismo , Animales , Aterosclerosis/genética , Antígenos CD36/genética , Antígenos CD36/metabolismo , Colesterol/metabolismo , Regulación de la Expresión Génica , Interleucina-1/genética , Lipoproteínas LDL/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Fosfatidilinositol 3-Quinasas/metabolismo , Placa Aterosclerótica/patología , Regiones Promotoras Genéticas/genética , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Transducción de Señal , Transcriptoma/genéticaRESUMEN
Early spontaneous detection of thrombin activation benefits precise theranostics for thrombotic vascular disease. Herein, a thrombin-responsive nanoprobe conjugated by a FITC dye, PEGylated Fe3O4 nanoparticles, and a thrombin-sensitive peptide (LASG) was constructed to visualize thrombin activation and subsequent thrombosis in vivo. The FITC dye was linked to the LASG coated on the Fe3O4 nanoparticles for sensing the thrombin activity via the Förster resonance energy transfer effect. In vitro fluorescence imaging showed that the fluorescence signal intensity increased significantly after incubation with thrombin in contrast to that of the control group (p < 0.05), and the signal intensity was enhanced with the increase in thrombin concentration. Further in vivo fluorescence imaging also revealed that the signal elevated markedly in the left common carotid artery (LCCA) lesion of the mice thrombosis model after nanoprobe injection, in contrast to that of the control + nanoprobe group (p < 0.05). Moreover, the thrombin inhibitor bivalirudin could decrease the filling defect of the LCCA. Three-dimensional fusion images of micro-CT and fluorescence confirmed that filling defects in the LCCA were nicely colocalized with fluorescence signal caused by nanoprobes. The nanoplatform based on a thrombin-activatable visualization system could provide smart responsive and dynamic imaging of thrombosis in vivo.
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Nanopartículas de Magnetita/química , Trombosis/diagnóstico por imagen , Trombosis/metabolismo , Secuencia de Aminoácidos , Animales , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Fluoresceína-5-Isotiocianato/química , Colorantes Fluorescentes/química , Imagen por Resonancia Magnética , Masculino , Ratones , Microscopía Confocal , Microscopía Fluorescente , Imagen Multimodal , Péptidos/química , Trombosis/patología , Tomografía Computarizada por Rayos XRESUMEN
Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer's disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD.
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Enfermedad de Alzheimer/genética , Proteínas del Citoesqueleto/genética , Trastornos de la Memoria/genética , MicroARNs/genética , Sinapsis/metabolismo , Quinasas Asociadas a rho/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Células Cultivadas , Proteínas del Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Hipocampo/citología , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/fisiología , Fosforilación , Transducción de Señal/genética , Transducción de Señal/fisiología , Sinapsis/fisiología , Quinasas Asociadas a rho/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Iron homeostasis disturbance has been implicated in Alzheimer's disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer's mouse model and Alzheimer's patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aß aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.
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Enfermedad de Alzheimer/genética , Ferroptosis/fisiología , Trastornos de la Memoria/genética , Animales , Modelos Animales de Enfermedad , Humanos , RatonesRESUMEN
OBJECTIVE: To observe the effects of the Bupi Hewei (BPHW) decoction on diarrhea and intestinal flora disorder induced by 5-fluorouracil (5-FU) and investigate the possible mechanism underlying these actions. METHODS: Thirty-five male Sprague-Dawley rats were randomly divided into four groups: normal control, 5-FU, 5-FU + BPHW decoction (10.5 g/kg for 5 consecutive days), and 5-FU + Bacillus licheniformis capsule groups (0.2 g/kg for 5 consecutive days). Animal models were established via the intraperitoneal injection of 5-FU (30 mg/kg for 5 consecutive days). At the end of the treatment period, diarrhea was assessed, and the change of the intestinal flora was examined using 16S rDNA high- throughput sequencing. Interleukin (IL)-17, IL-21, IL-6, IL-10, RAR-related orphan receptor gamma (RORγt), and forkhead box P3 (Foxp3) expression in the jejunum was detected using immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), Western blotting, and enzyme- linked immuno sorbent assay. RESULTS: In this study, the BPHW decoction effectively lowered the diarrhea score, increased the proportions of Bacteroidetes and Prevotellaceae-Alloprevotella species, and reduced the proportions of Proteobacteria, Escherichia-Shigella, Ruminococcaceae NK4A214, and Ruminococcaceae UCG-005 species in the rat intestine after 5-FU chemotherapy. In addition, the BPHW decoction significantly suppressed the expression of IL-17, IL-21, IL-6, IL-10, RORγt, and Foxp3 in the jejunum. CONCLUSION: Our findings suggest that the BPHW decoction can improve the intestinal immune balance and reduce intestinal inflammation by targeting T helper cell/T regulatory cell-associated factors.
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Disbiosis/tratamiento farmacológico , Fluorouracilo/efectos adversos , Intestinos/efectos de los fármacos , Intestinos/microbiología , Transducción de Señal/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Reguladores/citología , Animales , Disbiosis/inducido químicamente , Disbiosis/inmunología , Disbiosis/patología , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Yeyuno/microbiología , Masculino , Microbiota/efectos de los fármacos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Ratas , Ratas Sprague-Dawley , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
Tauopathies are a class of neurodegenerative diseases that are characterized by pathological aggregation of tau protein, which is accompanied by synaptic disorders. However, the role of tau in endocytosis, a fundamental process in synaptic transmission, remains elusive. Here, we report that forced expression of human tau (hTau) in mouse cortical neurons impairs endocytosis by decreasing the level of the GTPase dynamin 1 via disruption of the miR-132-MeCP2 pathway; this process can also be detected in the brains of Alzheimer's patients and hTau mice. Our results provide evidence for a novel role of tau in the regulation of presynaptic function.
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Dinamina I/metabolismo , Endocitosis , Proteína 2 de Unión a Metil-CpG/metabolismo , MicroARNs/metabolismo , Neuronas/metabolismo , Proteínas tau/genética , Enfermedad de Alzheimer/metabolismo , Animales , Endocitosis/genética , Humanos , Ratones , Proteínas tau/metabolismoRESUMEN
Rationale: Despite growing use of engineered nanomaterials (ENM) in applications from electronics to medicine, the potential risk to human health remains a critical concern within clinical use. ENM exposure during pregnancy can potentially cause reproductive toxicity even at levels that produce no measurable harm to animals in normal conditions. Methods: Phospholipid micelle-encapsulated CdSe/CdS/ZnS semiconductor nanocrystals with an average hydrodynamic diameter of 60 nm were intravenously injected during pregnancy in both rodent and nonhuman primate animal models. Cadmium concentration levels and maternal haematological and biochemical markers were determined, along with histopathological examination of major organs. Results: Nanocrystals were found to have crossed the placenta from mother to fetus in both rodents and nonhuman primates. However, the animal models display different responses with respect to reproductive toxicity. In the rodent model, toxicity symptoms are absent in treated subjects, with no observed gestational or fetal abnormalities and complications. A significantly higher miscarriage rate of 60% is recorded for macaques after prenatal nanoparticle administration. There was a miscarriage rate of 15% in the general population despite only ~0.16% of the initial cadmium dose present in the fetus. Blood and biochemical markers of treated macaques indicate acute hepatocellular injury within a week after nanoparticle administration. Histology of major organs of the miscarried macaque fetuses show no abnormalities. Conclusion: The potential of nanomaterials to cross the placenta and impact fetal survival in primates suggest the necessity of precautionary measures to prevent gestational exposure of ENMs.
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Aborto Espontáneo , Nanopartículas/toxicidad , Semiconductores/efectos adversos , Aborto Espontáneo/inducido químicamente , Aborto Espontáneo/metabolismo , Aborto Espontáneo/patología , Animales , Femenino , Humanos , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Placenta/metabolismo , Placenta/patología , EmbarazoRESUMEN
BuPiHeWei (BPHW) decoction, a classic Traditional Chinese Medicinal (TCM) prescription, has been widely used in clinical practice to relieve digestive symptoms caused by chemotherapy, such as diarrhea and vomiting. The present study aimed to investigate whether BPHW decoction exerted a protective role in the 5-Fu-induced intestinal mucosal injury in the rats by regulating the mechanisms of TLR-4/NF-κB signaling pathway. There were 35 Sprague Dawley rats randomly divided into four groups: normal control group, 5-Fu group, 5-Fu + BPHW decoction group (10.5 g/kg, for five continuous days), and 5-Fu + Bacillus licheniformis capsule group (0.2 g/kg, for five continuous days). Animal models were established by intraperitoneal injection of 5-Fu (30 mg/Kg, for five consecutive days). At the end of the treatment period, body weight, diarrhea score, and histological examination were examined. Furthermore, the expression of TLR-4/NF-κB pathway was detected to reveal its mechanism. The results showed that BPHW decoction effectively reduced diarrhea score and increased body weight and height of villi after 5-Fu chemotherapy. In addition, BPHW decoction could significantly inhibit the expression of TLR-4, NF-κB, and inflammatory factors (including TNF-α, IL-1ß, and IL-6) in the intestine, and the efficacy was significantly higher than that of Bacillus licheniformis capsule. In summary, BPHW decoction might be considered an effective drug to alleviate intestinal mucosal injury in the rats induced by 5-Fu.
RESUMEN
The potential health risks associated with heavy-metal containing quantum dots (QDs) are a major concern accompanying their increased application in both research and industry. In this contribution, we investigate the effects of QDs on reproductive outcomes in Kunming mice across three generations. Rather than being exposed to QDs during pregnancy, mice were intravenously injected with phospholipid micelle encapsulated CdSe/CdS/ZnS QDs at a dosage of 0.81 mg Cd/kg two weeks before mating. Four treatment groups were studied: non-injected control, female injected, male injected and both parents injected with QDs. Although QDs accumulated in the major organs of treated mice, we did not detect any pregnancy complications or adverse effects. No significant difference in pregnancy outcomes could be identified between the QD treated groups and the control group. More importantly, through behavior monitoring, blood tests and histological evaluations, two generations of the offspring were observed to be in normal and healthy condition. Our results show that QD exposure with a short buffering period before conception does not cause obvious pregnancy complications or significant toxicity effects in treated mice or their offspring. This indicates that a short buffering period after QD exposure may reduce potential risk of QDs to reproductive health.
RESUMEN
BACKGROUND: The prevalence of dyslipidemia is rising alarmingly in elderly Han Chinese male patients with type 2 diabetes mellitus (T2DM). The genetic factors that contribute to the development of diabetic dyslipidemia remain incompletely identified. This study was conducted to assess the association between vitamin D receptor (VDR) polymorphisms and development of dyslipidemia in the Han elderly male population with T2DM in North China. METHODS: A total of 242 T2DM patients with dyslipidemia (DH group, n=108) or without dyslipidemia (DO group, n=134) and 100 controls were genotyped for ApaI, TaqI and FokI single nucleotide polymorphisms (SNPs) of the VDR gene using polymerase chain reaction-restriction fragment length polymorphism and sequencing. The frequency and distribution of the SNPs were compared between cases and controls. RESULTS: The distribution of genotypes of VDR-FokI was significantly different between the control and DM group (P=0.033), as well as between the control and DH subgroup (P=0.011) but not DO subgroup (P=0.111). The frequency of C allele and CC genotype of FokI was significantly higher in the DH patients than in the controls (P=0.015 and P=0.003, respectively). Logistic regression analysis in a dominant model homozygous for the C allele of the FokI SNP showed that CC genotype was associated with DH patients (OR =1.797, 95% CI: 1.077-2.999, P=0.025). Significant associations of the ApaI and TaqI SNPs with either DO or DH subjects were not observed. CONCLUSION: These findings suggest that CC genotype of VDR-FokI is a risk factor for T2DM patients with dyslipidemia in elderly males in North China.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Dislipidemias/genética , Polimorfismo de Nucleótido Simple , Receptores de Calcitriol/genética , Anciano , Alelos , Estudios de Casos y Controles , China , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Factores de RiesgoRESUMEN
The aim of this study was to investigate the neuropathological features of the spinal cord in patients suffering with Alzheimer's disease (AD). Spinal cord tissue collected from three AD patients and eight controls was selected for the study. Data were collected at T2, T8, T10, L4, and S2 spinal levels. The sections were subjected to hematoxylin and eosin and Gallyas-Braak staining methods and then were immunostained with antibodies such as phosphorylated tau protein (AT8), α-synuclein, Aß, amyloid precursor protein, ubiquitin, and TDP-43. Pathological changes exhibited by the biomarkers were detected by microscopy. Neurofibrillary tangles (NFTs) were detectable in spinal anterior horn motor neurons in two of the three AD patients. AT8-positive axons or axon-like structures and AT8 expression in glial cells were detected in all three AD cases. Hyperphosphorylation of tau protein was detected in spinal anterior horn cells, glial cells, and axons, and its severity was associated with NFTs in the brain tissue. α-Synuclein-positive Lewy bodies and scattered Lewy-like neuritis were detected in the medial horn of the thoracic spinal cord and ventral sacral gray matter, respectively, in one patient who had AD with Lewy bodies. Neither amyloid deposition nor amyloid precursor protein and TDP-43 expression was detected in the spinal cord of AD patients. Spinal cord of AD patients was observed to contain phosphorylated tau protein and α-synuclein immunoreactive structures, which may play a role in dyskinesia and autonomic dysfunction in advanced AD.
RESUMEN
OBJECTIVE: To investigate histopathology and proteinopathy in the spinal cord of patients with common neurodegenerative diseases. METHODS: Spinal cord tissues from clinically and neuropathologically confirmed neruodegnerative diseases were enrolled in this study, including 3 cases of multiple system strophy, 4 cases of amyotrophic lateral sclerosis, 5 cases of Alzheimer's disease (AD, included 2 cases of AD combined with Parkinson's disease), 2 cases of progressive supranuclear palsy, 1 case of dementia with lewy body and 1 case of corticobasal degeneration from 1955 to 2013 at Chinese People's Liberation Army General Hospital. Four normal control cases were also included. Routine HE and Gallyas-Braak staining, and immunohistochemical stainings for anti-PHF tau (AT8), anti-α-synuclein, anti-TDP-43 and anti-ubiquitin were performed. RESULTS: Examination of the spinal cord in 3 cases with multiple system strophy revealed severe neuron loss in the intermediolateral nucleus of thoracic segment and Onuf's nucleus of the sacral segment, along with moderate neuron loss in the anterior horn of the cervical segment and mild myelin pallor in the anterior funiculus and anterolateral funiculus in the cervical and thoracic segments. Large amount of argentophilic, ubiquitin and synuclein positive oligodendroglial cytoplasmic inclusions were found widely distributed in the anterior horn and the anterior funiculus and anterolateral funiculus of the full spinal cord. Severe neuron loss and several morphological changes with gliosis in the anterior horn and severe loss of myelin in the anterior funiculus and anterolateral funiculus of the full spinal cord were observed in 4 cases of amyotrophic lateral sclerosis, 2 of which were found with Bunina bodies in neurons of the anterior horn. Three amyotrophic lateral sclerosis cases had ubiquitin-positive neuronal inclusions and TDP-43 positive neuronal and glial inclusions in the anterior horn at cervical and lumbar segments. A few argentophilic, tau positive neurofibrillary tangles (NFTs) and neuropil threads in the anterior horn at cervical and lumbar segments were found in 4 AD cases. Examination of spinal cord in 2 cases with Parkinson's disease combined with AD and 1 case with dementia with lewy body revealed severe neuron loss in the intermediolateral nucleus of thoracic segment, and a few synuclein positive lewy bodies and neuritis were also observed. There was mild neuron loss in the anterior horn at cervical and lumbar segments, along with some argentophilic, tau positive globous NFTs and many argentophilic, tau positive neutrophil threads were observed in 2 progressive supranuclear palsy cases and 1 corticobasal degeneration case. CONCLUSION: Each common neurodegenerative diseases of the spinal cord including multiple system strophy, amyotrophic lateral sclerosis and Parkinson's disease has its own specific histopathology and proteinopathy characteristics.