RESUMO
A new indole alkaloid, nauclorienine (1), along with seven known alkaloids (2-8), were isolated from the stems and leaves of Nauclea orientalis. Among them, nauclorienine (1) was a new indole alkaloid holding a rare corynanthe-type skeleton, and the known compounds (2-8) were isolated from N. orientalis for the first time. Their structures were elucidated on the basis of extensive spectroscopic data analyses. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Alkaloids 1-4 exhibited significant inhibitory effects against various human cancer cell lines with IC50 values comparable to those of cisplatin.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Alcaloides Indólicos/isolamento & purificação , Rubiaceae/química , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Estrutura Molecular , Extratos Vegetais/químicaRESUMO
Revealing the relationship between dysfunctional genes in blood and brain tissues from patients with Alzheimer's Disease (AD) will help us to understand the pathology of this disease. In this study, we conducted the first such large systematic analysis to identify differentially expressed genes (DEGs) in blood samples from 245 AD cases, 143 mild cognitive impairment (MCI) cases, and 182 healthy control subjects, and then compare these with DEGs in brain samples. We evaluated our findings using two independent AD blood datasets and performed a gene-based genome-wide association study to identify potential novel risk genes. We identified 789 and 998 DEGs common to both blood and brain of AD and MCI subjects respectively, over 77% of which had the same regulation directions across tissues and disease status, including the known ABCA7, and the novel TYK2 and TCIRG1. A machine learning classification model containing NDUFA1, MRPL51, and RPL36AL, implicating mitochondrial and ribosomal function, was discovered which discriminated between AD patients and controls with 85.9% of area under the curve and 78.1% accuracy (sensitivity = 77.6%, specificity = 78.9%). Moreover, our findings strongly suggest that mitochondrial dysfunction, NF-κB signalling and iNOS signalling are important dysregulated pathways in AD pathogenesis.
Assuntos
Doença de Alzheimer/genética , Biomarcadores/sangue , Biomarcadores/metabolismo , Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Sangue/metabolismo , Encéfalo/metabolismo , Estudos de Casos e Controles , Disfunção Cognitiva/sangue , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Aprendizado de Máquina , Mitocôndrias/genética , NF-kappa B/genética , Óxido Nítrico Sintase Tipo II/genética , Ribossomos/genética , Sensibilidade e Especificidade , Transdução de Sinais/genéticaRESUMO
Blood-based biomarkers for Alzheimer's disease would be very valuable because blood is a more accessible biofluid and is suitable for repeated sampling. However, currently there are no robust and reliable blood-based biomarkers for practical diagnosis. In this study we used a knowledge-based protein feature pool and two novel support vector machine embedded feature selection methods to find panels consisting of two and three biomarkers. We validated these biomarker sets using another serum cohort and an RNA profile cohort from the brain. Our panels included the proteins ECH1, NHLRC2, HOXB7, FN1, ERBB2, and SLC6A13 and demonstrated promising sensitivity (>87%), specificity (>91%), and accuracy (>89%).
Assuntos
Doença de Alzheimer/sangue , Proteoma/análise , Biomarcadores/sangue , Encéfalo/metabolismo , Isomerases de Ligação Dupla Carbono-Carbono/genética , Isomerases de Ligação Dupla Carbono-Carbono/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Bases de Conhecimento , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Sensibilidade e Especificidade , TranscriptomaRESUMO
Previous studies have evaluated gene expression in Alzheimer's disease (AD) brains to identify mechanistic processes, but have been limited by the size of the datasets studied. Here we have implemented a novel meta-analysis approach to identify differentially expressed genes (DEGs) in published datasets comprising 450 late onset AD (LOAD) brains and 212 controls. We found 3124 DEGs, many of which were highly correlated with Braak stage and cerebral atrophy. Pathway Analysis revealed the most perturbed pathways to be (a) nitric oxide and reactive oxygen species in macrophages (NOROS), (b) NFkB and (c) mitochondrial dysfunction. NOROS was also up-regulated, and mitochondrial dysfunction down-regulated, in healthy ageing subjects. Upstream regulator analysis predicted the TLR4 ligands, STAT3 and NFKBIA, for activated pathways and RICTOR for mitochondrial genes. Protein-protein interaction network analysis emphasised the role of NFKB; identified a key interaction of CLU with complement; and linked TYROBP, TREM2 and DOK3 to modulation of LPS signalling through TLR4 and to phosphatidylinositol metabolism. We suggest that NEUROD6, ZCCHC17, PPEF1 and MANBAL are potentially implicated in LOAD, with predicted links to calcium signalling and protein mannosylation. Our study demonstrates a highly injurious combination of TLR4-mediated NFKB signalling, NOROS inflammatory pathway activation, and mitochondrial dysfunction in LOAD.