RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba leaf and seed have been traditionally used in ancient China for the treatment of cough and asthma. However, there is limited literature available on the anti-COPD effects and mechanisms of Ginkgo biloba. AIMS OF THE STUDY: The aim of this study was to comprehensively investigate the therapeutic potential of ginkgo extracts in COPD through a combination of in vivo and in vitro functional experiments. Transcriptomic analyses were also employed to uncover novel molecular mechanisms underlying the therapeutic effects of ginkgetin in COPD. MATERIALS AND METHODS: The therapeutic efficacy of ginkgo extracts was assessed in a COPD model. The anti-inflammatory effects of ginkgetin and its underlying molecular mechanisms were examined in A549 cells treated with cigarette smoke extract (CSE). Additionally, transcriptomic analyses were conducted to identify novel molecular pathways influenced by ginkgetin. These findings were further validated using quantitative real-time polymerase chain reaction (qPCR) and Western blot techniques. RESULTS: The ethyl acetate extract of Ginkgo biloba L. seeds and ginkgetin treatment significantly reduced cytokine production in COPD mice. Following drug administration, lung function improved in different groups. The transcriptome data strongly supports the inhibitory effect of ginkgetin on CSE-induced inflammation through the downregulation of the c/EBPß signaling pathway and subsequent inhibition of CCL2 expression. CONCLUSION: Our results demonstrate that ginkgetin, one of the biflavones found in Ginkgo biloba, exhibits inhibitory effects on smoke-induced airway inflammation. This effect is achieved through the downregulation of the c/EBPß signaling pathway and the reduction of CCL2 expression.
Asunto(s)
Biflavonoides , Quimiocina CCL2 , Regulación hacia Abajo , Ginkgo biloba , Enfermedad Pulmonar Obstructiva Crónica , Transducción de Señal , Animales , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Biflavonoides/farmacología , Biflavonoides/uso terapéutico , Humanos , Transducción de Señal/efectos de los fármacos , Ginkgo biloba/química , Regulación hacia Abajo/efectos de los fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Ratones , Masculino , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Humo/efectos adversos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Células A549 , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Extracto de GinkgoRESUMEN
The present study aims to investigate the protective effects of N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (M 18:3) on corticosterone-induced neurotoxicity. A neurotoxic model was established by subcutaneous injection of corticosterone (40 mg per kg bw) for 21 days. Depressive behaviors (the percentage of sucrose consumption, the immobility time in the forced swimming test, and the total distance in the open field test) were observed. The levels of the brain-derived neurotrophic factor, the contents of tumor necrosis factor-α and interleukin-6, and the numbers of positive cells of doublecortin and bromodeoxyuridine in the hippocampus were measured. The density of hippocampal neurons was calculated. The morphological changes of hippocampal neurons (the density of dendritic spines, the dendritic length, and the area and volume of dendritic cell bodies) were observed. The expression levels of synaptophysin, synapsin I, and postsynaptic density protein 95 were measured. Behavioral experiments showed that M 18:3 (5 and 25 mg per kg bw) could remarkably improve the depressive behaviors. The enzyme-linked immunosorbent assay showed that M 18:3 could considerably reduce hippocampal neuroinflammation and increase hippocampal neurotrophy. Nissl staining showed that M 18:3 could remarkably improve the corticosterone-induced decrease in the hippocampal neuron density. Immunofluorescence analysis showed that M 18:3 could considerably promote hippocampal neurogenesis. Golgi staining showed that M 18:3 could remarkably improve the corticosterone-induced changes in the hippocampal dendritic structure. Western blotting showed that M 18:3 could considerably increase the expression levels of synaptic-structure-related proteins in the hippocampus. In conclusion, the protective effects of M 18:3 may be attributed to the anti-inflammatory, neurotrophic, and synaptic protection properties.
Asunto(s)
Alquenos/farmacología , Compuestos de Bencilo/farmacología , Hipocampo/efectos de los fármacos , Lepidium , Fármacos Neuroprotectores/farmacología , Alquenos/farmacocinética , Animales , Antiinflamatorios no Esteroideos/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Compuestos de Bencilo/farmacocinética , Barrera Hematoencefálica/metabolismo , Recuento de Células , Forma de la Célula , Corticosterona , Depresión/tratamiento farmacológico , Hipocampo/citología , Hipocampo/metabolismo , Hipocampo/fisiología , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neurogénesis , Neuronas/citología , Fármacos Neuroprotectores/farmacocinética , Extractos Vegetales/química , Extractos Vegetales/farmacocinética , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Sinapsis/efectos de los fármacos , Sinapsis/fisiologíaRESUMEN
Ginkgo biloba has long been used in ancient China for the treatment of cough, asthma, and other lung diseases. However, the active constituents in G. biloba for pulmonary disease treatment remain unclear. The objective of this study was to evaluate the anti-inflammatory active constituents in G. biloba and clarify their associated molecular mechanisms. The biological effects of different G. biloba extracts were evaluated in an ovalbumin-induced allergic mouse model. Anti-inflammatory compounds were present in the ethyl acetate phase of the extract, which were analysed by HPLC-MS. Biflavones were identified as the main compounds, which were further evaluated by docking calculations. Leukocyte elastase showed a high fit score with ginkgetin, one of the identified biflavones. The lowest binding free energy was -6.69 kcal mol-1. The effects of biflavones were investigated in vivo and in vitro. Ginkgetin markedly suppressed the abnormal expression of the Akt and p38 pathways in human neutrophil elastase (HNE)-stimulated A549 cells. Biflavones also decreased MUC5AC mRNA expression in HNE-stimulated A549 cells and the allergic mouse model. Inflammatory cells (neutrophils) and cytokines (IL-8) also decreased in mice treated with biflavones. The results suggest that G. biloba biflavones could inhibit the activity of leukocyte elastase. This in turn implicates G. biloba as a functional food for the treatment of airway inflammation.