RESUMEN
Brusatol is a butyrolactone compound isolated from traditional Chinese medicine Brucea javanica. It has been reported to possess strong cytotoxicity against various cancer cells, thus showing its potential as an anticancer drug. Besides, lipopolysaccharide (LPS) plays a central role in the tumor microenvironment, while epithelial-mesenchymal transformation (EMT), a biological process by which epithelial cells are transformed into mesenchymal phenotypic cells through specific procedures, participates in chronic inflammation and tumor metastasis. This study aimed to investigate the inhibition of LPS-induced tumor cell invasion and metastasis and the molecular mechanism of apoptosis induced by brusatol in human gastric cancer SGC-7901 cells. Cell viability, cell migration and invasion ability, inflammatory factor release, and protein expression were detected using methyl thiazolyl tetrazolium assays, transwell assays, ELISA kit, and Western blot analysis, respectively. The change of EMT marker protein vimentin was assessed using immunofluorescence, while the apoptosis rate was measured using flow cytometry. In summary, brusatol inhibited LPS-induced EMT via the deactivation of the PI3K/Akt/NF-кB signaling pathway. This provides a useful new theoretical basis for the treatment of gastric cancer in the future.
Asunto(s)
Lipopolisacáridos/farmacología , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Cuassinas/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/biosíntesis , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Interacciones Farmacológicas , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Lipopolisacáridos/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
Astragaloside IV (AS-IV), a natural product derived from Radix Astragali (Astragalus membranaceus), is beneficial for the treatment of Alzheimer's disease (AD), but the mechanisms underlying this benefit are not completely understood. Peroxisome proliferator-activated receptor gamma (PPARγ) and brain-derived neurotrophic factor (BDNF) are potential therapeutic targets for AD. In this study, we found that amyloid ß protein fragment 1-42 oligomers (AßO) suppressed BDNF and PPARγ expression, and inhibited tyrosine receptor kinase B (TrkB) phosphorylation in cultured hippocampal neurons; these changes were ameliorated by treatment with AS-IV. Inhibition of PPARγ by genetic and pharmacological methods also blocked the effect of AS-IV on BDNF expression in AßO-treated cells. Importantly, exogenous BDNF protected against neurotoxicity and apoptosis induced by AßO, whereas inhibition of PPARγ reversed protective effects of AS-IV against these outcomes. In vivo data further revealed that AS-IV improved AßO-induced memory impairment and reduced apoptosis of hippocampal neurons. Moreover, AS-IV suppressed the AßO-induced reduction in BDNF by promoting PPARγ activation in the hippocampus. Taken together, these results indicate that AS-IV prevents AßO-induced memory impairment and hippocampal neuronal apoptosis, probably by promoting the PPARγ/BDNF signaling pathway.
Asunto(s)
Apoptosis/efectos de los fármacos , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/prevención & control , Fármacos Neuroprotectores/farmacología , Saponinas/farmacología , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/metabolismo , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/uso terapéutico , PPAR gamma/metabolismo , Saponinas/uso terapéutico , Triterpenos/uso terapéuticoRESUMEN
Ferroptosis is a form of necrosis caused by iron-induced accumulation of lipid hydroperoxide, involving several molecular events, and has been implicated in Parkinson's disease. Gastrodin is a component of Gastrodia elata Blume with strong antioxidant activity. We examined whether gastrodin can prevent H2O2-induced cytotoxicity in rat glioma cell line C6. For this purpose, C6 cells were pretreated with gastrodin (1, 5, 25 µM) and then exposed to 100 µM H2O2. Results showed that pretreatment of C6 cells with gastrodin decreased H2O2-induced lactate dehydrogenase (LDH) release and cell death. Moreover, gastrodin decreased intracellular malondialdehyde (MDA) level, whereas increased glutathione peroxidase (GPX) activity and glutathione (GSH) level after H2O2 treatment. In addition, treatment of deferoxamine (DFO), ferrostatin-1, and liproxstatin-1 abolished ferroptosis induced by H2O2 or erastin pretreatment. Treatment with gastrodin attenuated H2O2-induced ferroptosis and decreased lipid reactive oxygen species (ROS) (C11-BODIPY) production in C6 cells. Moreover, gastrodin increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), GPX4, ferroportin-1 (FPN1), and heme oxygenase-1 (HO-1) in C6 cells treated with H2O2. RSL3, a GPX4 inhibitor, inhibited GPX4 protein level in cells co-treated with gastrodin and 100 µM H2O2. These findings indicate that gastrodin can inhibit H2O2-induced ferroptosis through its antioxidative effect in C6 cells.
Asunto(s)
Antioxidantes/farmacología , Alcoholes Bencílicos/farmacología , Ferroptosis/efectos de los fármacos , Glucósidos/farmacología , Peróxido de Hidrógeno/farmacología , Animales , Muerte Celular/efectos de los fármacos , Línea Celular , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
This work describes the preparation of a PEGylated niosomes-mediated drug delivery systems for Paeonol, thereby improving the bioavailability and chemical stability of Paeonol, prolonging its cellular uptake and enhancing its synergistic anti-cancer effects with 5-Fu. PEGylated niosomes, which are prepared from biocompatible nonionic surfactant of Spans 60 and cholesterol, and modified with PEG-SA. Pae-PEG-NISVs were evaluated in vitro and in vivo. The cytotoxicity of Pae-PEG-NISVs was investigated against HepG2 cells. Fluorescence microscope was used to detect the apoptotic morphological changes. Growth inhibition assays were carried out to investigate whether Pae-PEG-NISVs could enhance the antiproliferative effects of Pae co-treated with 5-FU on HepG2 cells. The optimized Pae-PEG-NISVs had mean diameters of approximately 166 nm and entrapment efficiency (EE) of 61.8%. Furthermore, the in vitro release study of Paeonol from PEGylated niosomes exhibited a relatively prolonged release profile for 12 h. Pharmacokinetic studies in rats after i.v. injection showed that Pae-PEG-NISVs had increased elimination half-lives (t1/2, 87.5 versus 17.0 min) and increased area under the concentration-time curve (AUC0-t, 38.0 versus 19.48 µg/ml*min) compared to Paeonol solution. Formulated Paeonol had superior cytotoxicity versus the free drug with IC50 values of 22.47 and 85.16 µg/mL at 24 h on HepG2 cells, respectively, and we found that low concentration of Pae-PEG-NISVs and 5-Fu in conjunction had obviously synergistic effect. Our results indicate that the PEG-NISVs system has the potential to serve as an efficient carrier for Paeonol by effectively solubilizing, stabilizing and delivering the drug to the cancer cells.