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Background: In recent years, the incidence and mortality rates of non-small cell lung cancer (NSCLC) have increased significantly. Shan Ci Gu is commonly used as an anticancer drug in traditional Chinese medicine; however, its specific mechanism against NSCLC has not yet been elucidated. Here, the mechanism was clarified through network pharmacology and molecular docking. Methods: The Traditional Chinese Medicine Systems Pharmacology database was searched for the active ingredients of Shan Ci Gu, and the relevant targets in the Swiss Target Prediction database were obtained according to the structure of the active ingredients. GeneCards were searched for NSCLC-related disease targets. We obtained the cross-target using VENNY to obtain the core targets. The core targets were imported into the Search Tool for the Retrieval of Interacting Genes/Proteins database, and Cytoscape software was used to operate a mesh chart. R software was used to analyze the Gene Ontology biological processes (BPs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The core targets and active compounds were molecularly docked through Auto-Dock Vina software to predict the detailed molecular mechanism of Shan Ci Gu for NSCLC treatment. We did a simple survival analysis with hub gene to assess the prognosis of NSCLC patients. Results: Three compounds were screened to obtain 143 target genes and 1,226 targets related to NSCLC, of which 56 genes were related to NSCLC treatment. Shan Ci Gu treatment for NSCLC involved many BPs and acted on main targets including epidermal growth factor receptor (EGFR), ESR1, and SRC through signaling pathways including the endocrine resistance, EGFR tyrosine kinase inhibitor resistance, and ErbB signaling pathways. Shan Ci Gu might be beneficial for treating NSCLC by inhibiting cell proliferation and migration. Molecular docking revealed that the active compounds ß-sitosterol, stigmasterol, and 2-methoxy-9,10-dihydrophenanthrene-4,5-diol had good affinity with the core target genes (EGFR, SRC, and ESR1). Core targets included EGFR, SRC, ESR1, ERBB2, MTOR, MCL1, matrix metalloproteinase 2 (MMP2), MMP9, KDR, and JAK2. Key KEGG pathways included endocrine resistance, EGFR tyrosine kinase inhibitor resistance, ErbB signaling, PI3K-Akt signaling, and Rap1 signaling pathways. These core targets and pathways have an inhibitory effect on the proliferation of NSCLC cells. Conclusion: Shan Ci Gu can treat NSCLC through a multi-target, multi-pathway molecular mechanism and effectively improve NSCLC prognosis. This study could serve as a reference for further mechanistic research on wider application of Shan Ci Gu for NSCLC treatment.
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Ficus hirta Vahl. (Wuzhimaotao) is an edible functional food used for the soup cooking and health products. Seven undescribed phenolic glycosides (1-7), along with 20 analogues, were isolated from the roots of Ficus hirta. Their structures were determined by comprehensive spectroscopic methods (UV, IR, HRESIMS, and NMR), while the absolute configuration of 1 was established by comparison of the experimental and calculated ECD data. The antineuroinflammatory effects of all the compounds were examined by Western blot. Compounds 1 and 11 attenuated the phosphorylation of AKT, JNK, and ERK1/2. In addition, compound 11 inhibited the NF-κB p65 phosphorylation. Our results indicated that compounds 1 and 11 decreased the occurrence of neuroinflammation in BV2 microglia cells, which might be regulated by inhibiting the activity of proteins in NF-κB, MAPK (JNK and ERK1/2), or AKT signaling pathways. Thus, 1 and 11 might exhibit antineuroinflammatory activities and show promise in treating neurodegenerative diseases.
Assuntos
Anti-Inflamatórios/química , Ficus/química , Glicosídeos/química , Microglia/efeitos dos fármacos , Fenóis/química , Extratos Vegetais/química , Raízes de Plantas/química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Descoberta de Drogas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , MAP Quinase Quinase 4/metabolismo , Microglia/citologia , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Emerging evidence indicates that certain microRNAs (miRNAs) play important roles in epileptogenesis. MiR-219 is a brain-specific miRNA and has been shown to negatively regulate the function of N-methyl-D-aspartate (NMDA) receptors by targeting Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)γ. Herein, we found that the level of miR-219 was decreased in both the kainic acid (KA)-induced epilepsy model and in cerebrospinal fluid specimens of epilepsy patients. Importantly, silencing of miR-219 by its antagomir in vivo resulted in seizure behaviors, abnormal cortical electroencephalogram (EEG) recordings in the form of high-amplitude and high-frequency discharges, and increased levels of CaMKIIγ and an NMDA receptor component, NR1, in a pattern similar to that found in KA-treated mice. Moreover, treatments with the miR-219 agomir in vivo alleviated seizures, abnormal EEG recordings, and decreased levels of CaMKIIγ and NR1 in KA-treated mice. Furthermore, treatment with MK-801, an antagonist of NMDA receptors, significantly alleviated abnormal EEG recordings induced by miR-219 antagomir. Together, these results demonstrate that miR-219 plays a crucial role in suppressing seizure formation in experimental models of epilepsy through modulating the CaMKII/NMDA receptor pathway and that miR-219 supplement may be a potential anabolic strategy for ameliorating epilepsy.
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Encéfalo/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/líquido cefalorraquidiano , Adolescente , Adulto , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , MicroRNAs/líquido cefalorraquidiano , Pessoa de Meia-Idade , Convulsões/diagnóstico , Convulsões/metabolismo , Adulto JovemRESUMO
Accumulation and deposition of amyloid-ß peptide (Aß) in the brain is a primary cause of the pathogenesis of Alzheimer's disease (AD). Aß is generated from amyloid-ß precursor protein (APP) through sequential cleavages first by ß-secretase and then by γ-secretase. Inhibiting ß-secretase activity is believed to be one of the most promising strategies for AD treatment. In the present study, we found that a resveratrol trimer, miyabenol C, isolated from stems and leaves of the small-leaf grape (Vitisthunbergii var. taiwaniana), can markedly reduce Aß and sAPPß levels in both cell cultures and the brain of AD model mice. Mechanistic studies revealed that miyabenol C affects neither protein levels of APP, the two major α-secretases ADAM10 and TACE, and the γ-secretase component Presenilin 1, nor γ-secretase-mediated Notch processing and TACE activity. In contrast, although miyabenol C has no effect on altering protein levels of the ß-secretase BACE1, it can inhibit both in vitro and in vivo ß-secretase activity. Together, our results indicate that miyabenol C is a prominent ß-secretase inhibitor and lead compound for AD drug development.