Accumulation of amyloid-β (Aβ), which results in the formation of senile plaques that cause oxidative damage and neuronal cell death, has been accepted as the major pathological mechanism of Alzheimer’s disease (AD). Hence, inhibition of Aβ-induced oxidative damage and neuronal cell apoptosis represents the effective strategies in combating AD. Ginsenoside Re (Re) has pharmacological effects against Aβ-induced neurotoxicity. However, its molecular mechanism remains elusive. The present study evaluated the effect of Re against Aβ-induced cytotoxicity and apoptosis in SH-SY5Y cells, and investigated the underlying mechanism. We demonstrate that Re inhibits the Aβ-triggered mitochondrial apoptotic pathway, as indicated by maintenance of mitochondrial functional, elevated Bcl-2/Bax ratio, reduced cytochrome c release, and inactivation of caspase-3/9. Re attenuated Aβ-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, and JNK activation. ROS-scavenging abrogated the ability of Re to alter ASK-1 activation. Simultaneously, inhibition of JNK abolished Re-induced Bax downregulation in Aβ-challenged SH-SY5Y cells. In addition, Re enhanced activation of the nuclear factor-E2-related factor 2 (Nrf2) in Aβ-induced SH-SY5Y cells. Knockdown of Nrf2 by small interfering RNA targeting Nrf2 abolished the protective effect of Re. Our findings indicate that Re could be a potential therapeutic approach for the treatment of AD.

No abstract

The aim of the present study was to examine the neuroprotective effects of a panel of active components of ginseng and to explore their molecular mechanisms of action in two rotenone (Rot)-induced models of Parkinson's disease: An in vitro model using the human neuroblastoma cell line SH-SY5Y and an in vivo model using Drosophila . Ginsenoside Re (Re) was identified as the most potent inhibitor of Rot-induced cytotoxicity in SH-SY5Y cells by Cell Counting kit-8 assay and lactate dehydrogenase release assay. Flow cytometry, Hoechst staining, Rhodamine 123 staining, ATP and cytochrome c release revealed that Re rescue of Rot-induced mitochondrial dysfunction and inhibition of the mitochondrial apoptotic pathway. Western blot analysis demonstrated that Re alleviated Rot-induced oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant pathway, and these effects were abolished by RNA interference-mediated knockdown of Nrf2. Re enhanced phosphorylation of components of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and extracellular regulated protein kinase (ERK) pathways, and pharmacological inhibition of these pathways reduced Re-mediated Nrf2 activation and neuroprotection. In the Drosophila model, Immunofluorescence microscopy, reactive oxygen species (ROS), hydrogen peroxide and knockdown analysis revealed that Re reversed Rot-induced motor deficits and dopaminergic neuron loss while concomitantly alleviating Rot-induced oxidative damage. The findings of the present study suggest that Re protects neurons against Rot-induced mitochondrial dysfunction and oxidative damage, at least in part, by inducing Nrf2/heme oxygenase-1 expression and activation of the dual PI3K/AKT and ERK pathways.

20(S)-Ginsenoside Rh2 [20(S)-GRh2], one of the main active components of Panax ginseng, induces apoptosis in a wide range of cancer cell types. The present study found that 20(S)-GRh2 reduces mitochondrial membrane potential, decreases adenosine triphosphate generation and induces reactive oxygen species in HeLa cervical cancer cells. In addition, 20(S)-GRh2 activated mitochondrion-dependent apoptosis and inhibited both mitochondrial oxidative phosphorylation and glycolysis in HeLa cells. It was found that voltage-dependent anion channel 1 (VDAC1) expression was significantly upregulated by 20(S)-GRh2 treatment, while hexokinase 2 expression was downregulated and segregated from the mitochondria. Furthermore, 20(S)-GRh2 promoted Bax transport from the cytoplasm to the mitochondria, and knockdown of VdAc1 inhibited Bax transport and apoptosis. These results suggest that VdAc1 is a novel target of 20(S)-GRh2. The present study provides a better understanding of the mechanistic link between cervical cancer metabolism and growth control, and these results may facilitate the development of new treatments for cervical cancer.

Ginsenoside Rh2 (G-Rh2) is a monomeric compound that extracted from ginseng and possesses anti-cancer activities both in vitro and in vivo . Previously, we reported that G-Rh2 induces apoptosis in HeLa cervical cancer cells and that the process was related to reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. However, the upstream mechanisms of G-Rh2, along with its cellular targets, remain to be elucidated. In the present study, the Cell Counting Kit-8 assay, flow cytometry and Hoechst staining revealed that G-Rh2 significantly inhibited cell viability and induced apoptosis of cervical cancer cells. However, G-Rh2 was demonstrated to be non-toxic to End1/e6e7 cells. JC-1, rhodamine 123 staining, oxidative phosphorylation and glycolysis capacity assays demonstrated that G-Rh2 exposure caused an immediate decrease in mitochondrial transmembrane potential due to its inhibition of mitochondrial oxidative phosphorylation, as well as glycolysis, both of which reduced cellular ATP production. Western blotting and electron transport chain (ETC) activity assays revealed that G-Rh2 significantly inhibited the activity of ETC complexes I, III and V. Overexpression of ETC complex III partially significantly restored mitochondrial ROS and inhibited the apoptosis of cervical cancer cells induced by G-Rh2. The predicted results of binding energy in molecular docking, confirmed that G-Rh2 was highly likely to induce mitochondrial ROS production and promote cell apoptosis by targeting the ETC complex, especially for ETC complex III. Taken together, the present results revealed the potential anti-cervical cancer activity of G-Rh2 and provide direct evidence for the contribution of impaired ETC complex activity to cervical cancer cell death.