Parkinson’s disease (PD) is a currently incurable neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and α-synuclein aggregation. Accumulated evidence indicates that the saponins, especially from ginseng, have neuroprotective effects against neurodegenerative disorders. Interestingly, saponin can also be found in marine organisms such as the sea cucumber, but little is known about its effect in neurodegenerative disease, including PD. In this study, we investigated the anti-Parkinson effects of frondoside A (FA) from Cucumaria frondosa and ginsenoside Rg3 (Rg3) from Panax notoginseng in C. elegans PD model. Both saponins were tested for toxicity and optimal concentration by food clearance assay and used to treat 6-OHDA-induced BZ555 and transgenic α-synuclein NL5901 strains in C. elegans. Treatment with FA and Rg3 significantly attenuated DAergic neurodegeneration induced by 6-OHDA in BZ555 strain, improved basal slowing rate, and prolonged lifespan in the 6-OHDA-induced wild-type strain with downregulation of the apoptosis mediators, egl-1 and ced-3, and upregulation of sod-3 and cat-2. Interestingly, only FA reduced α-synuclein aggregation, rescued lifespan in NL5901, and upregulated the protein degradation regulators, including ubh-4, hsf-1, hsp-16.1 and hsp-16.2. This study indicates that both FA and Rg3 possess beneficial effects in rescuing DAergic neurodegeneration in the 6-OHDA-induced C. elegans model through suppressing apoptosis mediators and stimulating antioxidant enzymes. In addition, FA could attenuate α-synuclein aggregation through the protein degradation process.
Chrysoeriol, a dietary methoxyflavonoid which is found in tropical medicinal plants, has been shown to have antioxidant, anti-inflammatory, and antineoplastic properties. The present study aimed to investigate the effects of chrysoeriol and its related mechanisms in rat C6 glioma cells. Cell viability in rat C6 glioma cells were measured by MTT assay. The protein expression levels of cleaved caspase-3, caspase-3, pro-apoptotic (Bax), anti-apoptotic protein (Bcl-2), and Annexin V were detected by Western blot analysis and immunocytochemical staining. Results showed that chrysoeriol significantly decreased cell viability and induced apoptosis in rat C6 glioma cells. Chrysoeriol significantly increased the levels of Bax/Bcl-2 ratio and cleaved caspase-3/caspase-3 ratio. Moreover, treatment with chrysoeriol significantly reduced the phosphorylation of PI3K, Akt, and mTOR expression in ratios. These results suggest that chrysoeriol promote apoptosis in rat C6 glioma cells via suppression of the PI3K/Akt/mTOR signaling pathway, thereby demonstrating the potential antineoplastic effects of chrysoeriol on glioma cells.
Glioblastoma (GBM) is the most commonly diagnosed type of brain cancer and the leading cause of brain cancer-related death. GBM contains a subpopulation of tumor-propagating glioblastoma stem-like cells that are thought to drive cancer progression and recurrence. Although several clinical trials are ongoing to explore new chemotherapeutic agents to treat GBM, the use of metformin (Met), a first-line drug for type 2 diabetes mellitus, in cancer remains controversial. Here, we show that combining Met with 9-cis retinoic acid (9-cis RA) reduced the proliferation rate of C6-GSCs (glioblastoma stem-like cells) in vitro. The results of flow cytometric analysis showed that treatment with 9-cis RA for 24 h induced 4.5% early and 38.0% late apoptosis in C6-GSCs. Twenty-four hours of Met treatment induced 23.6% early and 33.5% late apoptosis in C6-GSCs. Combination of Met and 9-cis RA treatment significantly increased both early and late apoptosis to 30.4% and 55.4%, respectively. The present findings suggest that not only 9-cis RA but also Met has the potential to induce early and late apoptotic GSCs death by affecting the functional cytoplasmic and nuclear organelles. At the protein level, there was increased cleaved caspase-3 but decreased procaspase-3 expression in Met-, 9-cis RA- and Met+9-cis RA-treated C6 GSCs, as detected by western blotting. The ratio of cleaved caspase-3/procaspase-3 was 1.6 times higher in Met+9-cis RA-treated groups compared to control. Ultimately, a combination of Met and 9-cis RA might be a possible therapeutic target for the treatment of GBM.
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