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Viruses have evolved sophisticated mechanisms to manipulate host cell processes and utilize intracellular organelles to facilitate their replication. These complex interactions between viruses and cellular organelles allow them to hijack the cellular machinery and impair homeostasis. Moreover, viral infection alters the cell membrane's structure and composition and induces vesicle formation to facilitate intracellular trafficking of viral components. However, the research focus has predominantly been on the immune response elicited by viruses, often overlooking the significant alterations that viruses induce in cellular organelles. Gaining a deeper understanding of these virus-induced cellular changes is crucial for elucidating the full life cycle of viruses and developing potent antiviral therapies. Exploring virus-induced cellular changes could substantially improve our understanding of viral infection mechanisms.
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Virosis , Replicación Viral , Humanos , Orgánulos/ultraestructura , Interacciones Huésped-PatógenoRESUMEN
BACKGROUND: The relationship between allergic and eosinophilic inflammation, either systemic or local, in allergic diseases remains unclear. OBJECTIVE: We performed combined genome-wide association study (GWAS) and epigenome-wide (EWAS) for atopy and tissue eosinophilia to identify both genetic and epigenetic signatures between systemic and local allergic inflammation, and to capture global patterns of gene regulation. METHODS: We included 126 subjects for atopy analysis and 147 for tissue eosinophilia analysis, as well as 18 normal nasal tissue samples. We identified differentially methylated positions (DMPs) and genes associated with atopy and tissue eosinophilia. Furthermore, we performed mendelian randomization analysis and penalized regression along with replication in an independent cohort. RESULTS: EWAS identified genes, including Musashi RNA binding protein 2 (MSI2), associated with atopy, which contained enriched DMPs that genetically affect atopy. A direct association was observed between MSI2 single-nucleotide polymorphisms and atopy, as was a causal effect of changes in MSI2 expression and methylation on atopy, which was replicated in a Costa Rican population. Regarding tissue eosinophilia, EWAS identified genes with enriched DMPs directly contributing to tissue eosinophilia at the gene level, including CAMK1D. The gene ontology terms of the identified genes for both phenotypes encompassed immune-related terms. CONCLUSION: EWAS combined with GWAS identified novel candidate genes, especially the methylation of MSI2, contributing to systemic allergic inflammation. Certain genes displayed a greater association with either systemic or local allergic inflammation; however, it is expected that a harmonized effect of these genes influences immune responses.
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Eosinofilia/genética , Hipersensibilidad/genética , Proteínas de Unión al ARN/genética , Adulto , Metilación de ADN , Epigénesis Genética , Epigenoma , Femenino , Ontología de Genes , Estudio de Asociación del Genoma Completo , Humanos , Inflamación/genética , Masculino , Persona de Mediana Edad , Mucosa Nasal , Polimorfismo de Nucleótido SimpleRESUMEN
Based on the hypothesis that the variation of the metabolomes of latex is a response to selective pressure and should thus be affected differently from other organs, their variation could provide an insight into the defensive chemical selection of plants. Metabolic profiling was used to compare tissues of three Euphorbia species collected in diverse regions. The metabolic variation of latexes was much more limited than that of other organs. In all the species, the levels of polyisoprenes and terpenes were found to be much higher in latexes than in leaves and roots of the corresponding plants. Polyisoprenes were observed to physically delay the contact of pathogens with plant tissues and their growth. A secondary barrier composed of terpenes in latex and in particular, 24-methylenecycloartanol, exhibited antifungal activity. These results added to the well-known role of enzymes also present in latexes, show that these are part of a cooperative defense system comprising biochemical and physical elements.
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Euphorbia/metabolismo , Euphorbia/microbiología , Geografía , Herbivoria , Látex/metabolismo , Metabolómica , Euphorbia/fisiología , Especificidad de la EspecieRESUMEN
Mass spectrometry-based molecular imaging has been utilized to map the spatial distribution of target metabolites in various matrixes. Among the diverse mass spectrometry techniques, matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) is the most popular for molecular imaging due to its powerful spatial resolution. This unparalleled high resolution, however, can paradoxically act as a bottleneck when the bio-imaging of large areas, such as a whole plant, is required. To address this issue and provide a more versatile tool for large scale bio-imaging, direct analysis in real-time-time of flight-mass spectrometry (DART-TOF-MS), an ambient ionization MS, was applied to whole plant bio-imaging of a medicinal plant, Ephedrae Herba. The whole aerial part of the plant was cut into 10-20 cm long pieces, and each part was further cut longitudinally to compare the contents of major ephedra alkaloids between the outer surface and inner part of the stem. Using optimized DART-TOF-MS conditions, molecular imaging of major ephedra alkaloids of the whole aerial part of a single plant was successfully achieved. The concentration of alkaloids analyzed in this study was found to be higher on the inner section than the outer surface of stems. Moreover, side branches, which are used in traditional medicine, represented a far higher concentration of alkaloids than the main stem. In terms of the spatial metabolic distribution, the contents of alkaloids gradually decreased towards the end of branch tips. In this study, a fast and simple macro-scale MS imaging of the whole plant was successfully developed using DART-TOF-MS. This application on the localization of secondary metabolites in whole plants can provide an area of new research using ambient ionization mass spectroscopy and an unprecedented macro-scale view of the biosynthesis and distribution of active components in medicinal plants.
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Alcaloides/metabolismo , Ephedra/metabolismo , Espectrometría de Masas/métodos , Plantas Medicinales/metabolismo , Efedrina/análogos & derivados , Efedrina/metabolismo , Espectrometría de Masas/instrumentación , Imagen Molecular/instrumentación , Imagen Molecular/métodos , Componentes Aéreos de las Plantas/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
(S)-Allyl-l-cysteine is the major bioactive compound in garlic. (S)-Allyl-l-cysteine is metabolized to (S)-allyl-l-cysteine sulfoxide, N-acetyl-(S)-allyl-l-cysteine, and N-acetyl-(S)-allyl-l-cysteine sulfoxide after oral administration. An accurate LC-MS/MS method was developed and validated for the simultaneous quantification of (S)-allyl-l-cysteine and its metabolites in rat plasma, and the feasibility of using it in pharmacokinetic studies was tested. The analytes were quantified by multiple reaction monitoring using an atmospheric pressure ionization mass spectrometer. Because significant quantitative interference was observed between (S)-allyl-l-cysteine and N-acetyl-(S)-allyl-l-cysteine as a result of the decomposition of N-acetyl-(S)-allyl-l-cysteine at the detector source, chromatographic separation was required to discriminate (S)-allyl-l-cysteine and its metabolites on a reversed-phase C18 analytical column with a gradient mobile phase consisting of 0.1% formic acid and acetonitrile. The calibration curves of (S)-allyl-l-cysteine, (S)-allyl-l-cysteine sulfoxide, N-acetyl-(S)-allyl-l-cysteine, and N-acetyl-(S)-allyl-l-cysteine sulfoxide were linear over each concentration range, and the lower limits of quantification were 0.1 µg/mL [(S)-allyl-l-cysteine and N-acetyl-(S)-allyl-l-cysteine] and 0.25 µg/mL [(S)-allyl-l-cysteine sulfoxide and N-acetyl-(S)-allyl-l-cysteine sulfoxide]. Acceptable intraday and inter-day precisions and accuracies were obtained at three concentration levels. The method satisfied the regulatory requirements for matrix effects, recovery, and stability. The validated LC-MS/MS method was successfully used to determine the concentration of (S)-allyl-l-cysteine and its metabolites in rat plasma samples after the administration of (S)-allyl-l-cysteine or aged garlic extract.
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Cromatografía Líquida de Alta Presión/métodos , Cisteína/análogos & derivados , Ajo/química , Espectrometría de Masas/métodos , Extractos Vegetales/metabolismo , Administración Oral , Animales , Cisteína/administración & dosificación , Cisteína/química , Cisteína/metabolismo , Cisteína/farmacocinética , Masculino , Estructura Molecular , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Extractos Vegetales/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
In this study, we investigated the antiinflammatory effects of ethanol extracts of Potentilla. supina Linne (EPS) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and septic mice. EPS suppressed LPS-induced nitric oxide, prostaglandin E2 , TNF-α, interleukin-6 and interleukin-1ß at production and mRNA levels in LPS-induced RAW 264.7 macrophages. Consistent with these observations, EPS attenuated the expressions of inducible nitric oxide synthase and cyclooxygenase-2 by downregulation of their promoter activities. Molecularly, EPS reduced the LPS-induced transcriptional activity and DNA-binding activity of nuclear factor-κB (NF-κB), and this was associated with a decrease of translocation and phosphorylation of p65 NF-κB by inhibiting the inhibitory κB-α degradation and IKK-α/ß phosphorylation. Furthermore, EPS inhibited the LPS-induced activation of activator protein-1 by reducing the expression of c-Fos and c-Jun in nuclear. EPS also suppressed the phosphorylation of mitogen-activated protein kinase, such as p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. In an LPS-induced endotoxemia mouse model, pretreatment with EPS reduced the mRNA levels of inducible nitric oxide synthase, cyclooxygenase-2 and proinflammatory cytokines and increased the survival rate of mice. Collectively, these results suggest that the antiinflammatory effects of EPS were associated with the suppression of NF-κB and activator protein-1 activation and support its possible therapeutic role for the treatment of endotoxemia. Copyright © 2017 John Wiley & Sons, Ltd.
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Antiinflamatorios/farmacología , Etanol/química , Inflamación/prevención & control , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Extractos Vegetales/farmacología , Potentilla/química , Choque Séptico/tratamiento farmacológico , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/uso terapéutico , Línea Celular , Citocinas/metabolismo , Endotoxinas , Etanol/farmacología , Inflamación/inducido químicamente , Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Choque Séptico/inducido químicamente , Choque Séptico/inmunología , Choque Séptico/metabolismo , Factor de Transcripción AP-1/antagonistas & inhibidores , Factor de Transcripción AP-1/metabolismoRESUMEN
Species demarcation in Bacteria and Archaea is mainly based on overall genome relatedness, which serves a framework for modern microbiology. Current practice for obtaining these measures between two strains is shifting from experimentally determined similarity obtained by DNA-DNA hybridization (DDH) to genome-sequence-based similarity. Average nucleotide identity (ANI) is a simple algorithm that mimics DDH. Like DDH, ANI values between two genome sequences may be different from each other when reciprocal calculations are compared. We compared 63 690 pairs of genome sequences and found that the differences in reciprocal ANI values are significantly high, exceeding 1 % in some cases. To resolve this problem of not being symmetrical, a new algorithm, named OrthoANI, was developed to accommodate the concept of orthology for which both genome sequences were fragmented and only orthologous fragment pairs taken into consideration for calculating nucleotide identities. OrthoANI is highly correlated with ANI (using BLASTn) and the former showed approximately 0.1 % higher values than the latter. In conclusion, OrthoANI provides a more robust and faster means of calculating average nucleotide identity for taxonomic purposes. The standalone software tools are freely available at http://www.ezbiocloud.net/sw/oat.
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A Gram-stain negative, rod-shaped, non-spore-forming, obligate aerobic bacterial strain, JC2949(T), was isolated from grassland soil in Gwanak Mountain, Seoul, Republic of Korea. Phylogenetic analysis, based on 16S rRNA sequences, indicated that strain JC2949(T) belongs to the genus Burkholderia, showing highest sequence similarities with Burkholderia grimmiae R27(T) (98.8â%), Burkholderia cordobensis LMG 27620(T) (98.6â%), Burkholderia jiangsuensis MP-1T(T) (98.6â%), Burkholderia zhejiangensis OP-1(T) (98.5â%), Burkholderia humi LMG 22934(T) (97.5â%), Burkholderia terrestris LMG 22937(T) (97.3â%), Burkholderia telluris LMG 22936(T) (97.2â%) and Burkholderia glathei ATCC 29195(T) (97.0â%). The major fatty acids of strain JC2949(T) were C18â:â1ω7c, summed feature 3 (C16â:â1ω7c and/or C16â:â1ω6c) and C16â:â0. Its predominant polar lipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and an unknown amino phospholipid. The dominant isoprenoid quinone was ubiquinone Q-8. The pairwise average nucleotide identity values between strain JC2949(T) and the genomes of 30 other species of the genus Burkholderia ranged from 73.4-90.4â%, indicating that the isolate is a novel genomic species within this genus. Based on phenotypic and chemotaxonomic comparisons, it is clear that strain JC2949(T) represents a novel species of the genus Burkholderia. We propose the name for this novel species to be Burkholderia megalochromosomata sp. nov. The type strain is JC2949(T) (â=âKACC 17925(T)â=âJCM 19905(T)).
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Burkholderia/clasificación , Pradera , Filogenia , Microbiología del Suelo , Técnicas de Tipificación Bacteriana , Composición de Base , Burkholderia/genética , Burkholderia/aislamiento & purificación , ADN Bacteriano/genética , Ácidos Grasos/química , Datos de Secuencia Molecular , Fosfolípidos/química , ARN Ribosómico 16S/genética , República de Corea , Análisis de Secuencia de ADN , Ubiquinona/químicaRESUMEN
Among available genome relatedness indices, average nucleotide identity (ANI) is one of the most robust measurements of genomic relatedness between strains, and has great potential in the taxonomy of bacteria and archaea as a substitute for the labour-intensive DNA-DNA hybridization (DDH) technique. An ANI threshold range (95-96%) for species demarcation had previously been suggested based on comparative investigation between DDH and ANI values, albeit with rather limited datasets. Furthermore, its generality was not tested on all lineages of prokaryotes. Here, we investigated the overall distribution of ANI values generated by pairwise comparison of 6787 genomes of prokaryotes belonging to 22 phyla to see whether the suggested range can be applied to all species. There was an apparent distinction in the overall ANI distribution between intra- and interspecies relationships at around 95-96% ANI. We went on to determine which level of 16S rRNA gene sequence similarity corresponds to the currently accepted ANI threshold for species demarcation using over one million comparisons. A twofold cross-validation statistical test revealed that 98.65% 16S rRNA gene sequence similarity can be used as the threshold for differentiating two species, which is consistent with previous suggestions (98.2-99.0%) derived from comparative studies between DDH and 16S rRNA gene sequence similarity. Our findings should be useful in accelerating the use of genomic sequence data in the taxonomy of bacteria and archaea.
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Archaea/clasificación , Bacterias/clasificación , Genómica/métodos , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN/métodos , Archaea/genética , Bacterias/genética , Hibridación de Ácido Nucleico/métodosRESUMEN
EzEditor is a Java-based molecular sequence editor allowing manipulation of both DNA and protein sequence alignments for phylogenetic analysis. It has multiple features optimized to connect initial computer-generated multiple alignment and subsequent phylogenetic analysis by providing manual editing with reference to biological information specific to the genes under consideration. It provides various functionalities for editing rRNA alignments using secondary structure information. In addition, it supports simultaneous editing of both DNA sequences and their translated protein sequences for protein-coding genes. EzEditor is, to our knowledge, the first sequence editing software designed for both rRNA- and protein-coding genes with the visualization of biologically relevant information and should be useful in molecular phylogenetic studies. EzEditor is based on Java, can be run on all major computer operating systems and is freely available from http://sw.ezbiocloud.net/ezeditor/.
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ARN Ribosómico/genética , Alineación de Secuencia/métodos , Programas Informáticos , Secuencia de Aminoácidos , Secuencia de Bases , Biología Computacional , Filogenia , Lenguajes de ProgramaciónRESUMEN
Listening to music is a crucial tool for relieving stress and promoting relaxation. However, the limited options available for stress-relief music do not cater to individual preferences, compromising its effectiveness. Traditional methods of curating stress-relief music rely heavily on measuring biological responses, which is time-consuming, expensive, and requires specialized measurement devices. In this paper, a deep learning approach to solve this problem is introduced that explicitly uses convolutional neural networks and provides a more efficient and economical method for generating large datasets of stress-relief music. These datasets are composed of Mel-scaled spectrograms that include essential sound elements (such as frequency, amplitude, and waveform) that can be directly extracted from the music. The trained model demonstrated a test accuracy of 98.7%, and a clinical study indicated that the model-selected music was as effective as researcher-verified music in terms of stress-relieving capacity. This paper underlines the transformative potential of deep learning in addressing the challenge of limited music options for stress relief. More importantly, the proposed method has profound implications for music therapy because it enables a more personalized approach to stress-relief music selection, offering the potential for enhanced emotional well-being.
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Musicoterapia , Música , Redes Neurales de la Computación , Estrés Psicológico , Humanos , Música/psicología , Estrés Psicológico/terapia , Musicoterapia/métodos , Aprendizaje Profundo , Masculino , Femenino , Adulto , Espectrografía del Sonido/métodos , Adulto JovenRESUMEN
A Gram-stain-negative, rod-shaped, pale yellow, aerobic bacterial strain, JC2902(T), was isolated from a sediment sample of Ungok Lake in Gochang, Republic of Korea. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain JC2902(T) belongs to the genus Flavobacterium and forms a distinct phyletic line within a clade containing four recognized species of the genus Flavobacterium. The genomic relatedness between strain JC2902(T) and closely related strains was calculated using average nucleotide identity values of whole genome sequences, which indicated that the new isolate represents a novel genomic species. Through comparison of chemotaxonomic and other phenotypic characteristics between strain JC2902(T) and the type strains of the four phylogenetically related species, a number of characteristics differentiated strain JC2902(T) from the previously described type strains. Differential characteristics of strain JC2902(T) include fatty acid profiles, cellular motility, inability to grow on Luria-Bertani and tripticase soy agar media, and absence of N-acetyl-ß-glucosaminidase and flexirubin-type pigments. Based on data from this polyphasic taxonomic study, strain JC2902(T) is considered to represent a novel species of the genus Flavobacterium, for which the name Flavobacterium limnosediminis sp. nov. is proposed. The type strain is JC2902(T) (â=âKACC 16937(T)â=âJCM 18661(T)).
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Flavobacterium/clasificación , Sedimentos Geológicos/microbiología , Lagos/microbiología , Filogenia , Composición de Base , ADN Bacteriano/genética , Ácidos Grasos/química , Flavobacterium/genética , Flavobacterium/aislamiento & purificación , Datos de Secuencia Molecular , Polienos/química , ARN Ribosómico 16S/genética , República de Corea , Análisis de Secuencia de ADNRESUMEN
Objective: We aimed to investigate the effect of internet-based and in-person cognitive interventions on cognition, mood, and activities of daily living (ADL) on patients with mild to moderate Alzheimer's disease (AD) and examine whether internet-based intervention is as effective as the in-person intervention. Methods: We recruited 52 patients with probable mild AD, of whom 42 completed the trial. We randomly divided participants into intervention and control groups at a 1:1 ratio and statistically compared the neuropsychological test results of the two groups. In addition, patients in the intervention group were randomly assigned to a 4 weeks internet-based or in-person intervention, with subsequent crossover to the other group for 4 weeks. We statistically analyzed and compared the neuropsychological test scores between internet-based and in-person interventions. Results: Compared with the control group, the intervention group (internet-based and in-person) showed significantly improved profile in cognition (p < 0.001), depression (p < 0.001), anxiety (p < 0.001) and ADL (p < 0.001). In addition, the effect of the internet-based intervention on cognition (p = 0.918) and depression (p = 0.282) was not significantly different from that of the in-person intervention. However, in the Beck anxiety inventory (p = 0.009) and Seoul instrumental activity of daily living (p = 0.023), in-person intervention was more effective than internet-based intervention. Conclusion: This study suggests that both types of cognitive intervention (in-person and internet-based) may be viable supplementary treatments along with approved pharmacological therapy. In terms of anxiety and ADL, the effect of the in-person interventions may be more effective than the-internet based interventions.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/terapia , Actividades Cotidianas , Cognición , Ansiedad , InternetRESUMEN
Despite recent advances in commercially optimized identification systems, bacterial identification remains a challenging task in many routine microbiological laboratories, especially in situations where taxonomically novel isolates are involved. The 16S rRNA gene has been used extensively for this task when coupled with a well-curated database, such as EzTaxon, containing sequences of type strains of prokaryotic species with validly published names. Although the EzTaxon database has been widely used for routine identification of prokaryotic isolates, sequences from uncultured prokaryotes have not been considered. Here, the next generation database, named EzTaxon-e, is formally introduced. This new database covers not only species within the formal nomenclatural system but also phylotypes that may represent species in nature. In addition to an identification function based on Basic Local Alignment Search Tool (blast) searches and pairwise global sequence alignments, a new objective method of assessing the degree of completeness in sequencing is proposed. All sequences that are held in the EzTaxon-e database have been subjected to phylogenetic analysis and this has resulted in a complete hierarchical classification system. It is concluded that the EzTaxon-e database provides a useful taxonomic backbone for the identification of cultured and uncultured prokaryotes and offers a valuable means of communication among microbiologists who routinely encounter taxonomically novel isolates. The database and its analytical functions can be found at http://eztaxon-e.ezbiocloud.net/.
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Archaea/clasificación , Archaea/genética , Bacterias/clasificación , Bacterias/genética , Bases de Datos de Ácidos Nucleicos , Genes de ARNr , ARN Ribosómico 16S/genética , Clasificación/métodos , Biología Computacional/métodosRESUMEN
Aspergillus cristatus is a beneficial fungus of microbial fermented teas such as China's Fuzhuan brick tea and Pu-erh tea, and is commonly called golden flower fungus (GFF) because its cleistothecium has a yellow millet or sand grain shape. Since natural materials fermented with GFF exhibit various physiological activities, a new active cosmeceutical ingredient was developed by solid-state fermentation of ginseng, a famous active material for healthy skin, with GFF. The extract of solid-state fermented ginseng with GFF (GFFG) exhibited potent anti-aging efficacy on the skin such as the increase of hyaluronic acid synthesis, aquaporin expression, and mRNA level of filaggrin in HaCaT keratinocyte. GFFG also inhibited the expression of MMP-1 increased by TNF-α in human dermal fibroblast. Sophisticated chromatographic and spectroscopic studies have elucidated isodihydroauroglaucin and flavoglaucin as the metabolites which were not present in ginseng extract nor GFF extract alone. Bioassay of these metabolites revealed that these compounds were part of active principles of GFFG. These results suggest that GFFG would be a potential active ingredient in anti-aging cosmeceutical products.
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Parkinson's disease (PD) is the second most common neurodegenerative disease, after Alzheimer's disease, and becomes increasingly prevalent with age. α-Synuclein (α-syn) forms the major filamentous component of Lewy bodies, which are pathological hallmarks of α-synucleinopathies such as PD. We evaluated the neuroprotective effects of MT101-5, a standardized herbal formula that consists of an ethanolic extract of Genkwae Flos, Clematidis Radix, and Gastrodiae Rhizoma, against α-synuclein-induced cytotoxicity in vivo. MT101-5 protected against behavioral deficits and loss of dopaminergic neurons in human α-syn-overexpressing transgenic mice after treatment with 30 mg/kg/day for 5 months. We investigated transcriptomic changes within MT101-5 mechanisms of action (MOA) suppressing α-syn aggregation in an α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic PD. We found that inhibition of α-syn fibril formation was associated with changes in transcripts in mitochondrial biogenesis, electron transport, chaperones, and proteasomes following treatment with MT101-5. These results suggest that the mixed herbal formula MT101-5 may be used as a pharmaceutical agent for preventing or improving PD.
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Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Humanos , Ratones , Ratones Transgénicos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , alfa-SinucleínaRESUMEN
Neuroinflammation, which occurs due to microglia, is related to the pathogenesis of neurodegenerative disorders. Recently, the development of functional foods that down-regulate over-activated microglial cells to prevent the progression of neurodegenerative disorders has been proposed, since over-activated microglia induce a chronic source of neurotoxic factors and reduce neuronal survival. Thus, the anti-neuroinflammatory effects of a functional food mixture (CCL01) including Cuscuta seeds and Lactobacillus paracasei NK112 on lipopolysaccharide (LPS)-induced experimental models were investigated. In LPS-induced in vitro models, the expression levels of inflammatory mediators (e.g., inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, and prostaglandin E2) and pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6) were decreased upon CCL01 treatment. CCL01 showed an anti-neuroinflammatory effect in LPS-induced microglial cells via the inhibition of the mitogen-activated protein kinase (MAPK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and the activation of the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. In the LPS-treated in vivo mouse models, the increased expression of ionized calcium binding adaptor molecule 1 (Iba-1), which indicates microglial activity, was markedly decreased upon treatment with CCL01 (50 and 200 mg kg-1) in the hippocampus and cortex areas of the mouse brains in comparison with the LPS-injected group. In addition, the groups to which CCL01 was administered had significantly decreased plasma levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in the LPS-injected mouse models. Our data suggest that CCL01 may be a potential anti-neuroinflammatory agent that can prevent microglia overactivation, and it could be useful for developing functional foods.
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Cuscuta , Lacticaseibacillus paracasei , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Cuscuta/metabolismo , Alimentos Funcionales , Interleucina-6/metabolismo , Lacticaseibacillus paracasei/metabolismo , Lipopolisacáridos/farmacología , Ratones , Microglía , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/metabolismo , Extractos Vegetales/farmacología , Semillas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Background and Objectives: While somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms. Methods: We performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results. Results: Somatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in the SVIL gene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown of SVIL via the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found that SVIL regulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway. Discussion: We propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants in SVIL result in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.
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OBJECTIVE: This article presents a new computerized scheme that aims to accurately and robustly separate left and right lungs on computed tomography (CT) examinations. METHODS: We developed and tested a method to separate the left and right lungs using sequential CT information and a guided dynamic programming algorithm using adaptively and automatically selected start point and end point with especially severe and multiple connections. RESULTS: The scheme successfully identified and separated all 827 connections on the total 4034 CT images in an independent testing data set of CT examinations. The proposed scheme separated multiple connections regardless of their locations, and the guided dynamic programming algorithm reduced the computation time to approximately 4.6% in comparison with the traditional dynamic programming and avoided the permeation of the separation boundary into normal lung tissue. CONCLUSIONS: The proposed method is able to robustly and accurately disconnect all connections between left and right lungs, and the guided dynamic programming algorithm is able to remove redundant processing.