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Parkinson's disease (PD) is a neurological disorder pathologically characterized by loss of dopaminergic neurons in the substantia nigra. No curative therapy is available for PD. We recently found that phytoestrogen β-ecdysterone (β-Ecd) is able to reduce MPP(+)-induced apoptosis in PC12 cells. This study investigated the potential of β-Ecd to protect against SH-SY5Y cell apoptosis induced by the PD-related neurotoxin 6-hydroxydopamine (6-OHDA) and the underlying mechanism for this cytoprotection. In the present study, pretreatment with β-Ecd significantly reduced 6-OHDA-induced apoptosis of SH-SY5Y cells by a mitochondria-dependent pathway, as indicated by downregulation of Bax and PUMA (p53 upregulated modulator of apoptosis) expression, suppressing ΔΨm loss, inhibiting cytochrome c release, and attenuating caspase-9 activation. Furthermore, we showed that the inhibition of p38 mitogen-activated protein kinase (p38(MAPK))-dependent p53 promoter activity contributed to the protection of SH-SY5Y cells from apoptosis, which was validated by the use of SB203580 or p38β dominant negative (DN) mutants. Additionally, knock-down apoptosis signal-regulating kinase 1 (ASK1) by specific shRNA and blockade reactive oxygen species (ROS) by pharmacological inhibitor competently prevented β-Ecd-mediated inhibition of p38(MAPK) and ASK1 phosphorylation, respectively. These data provide the first evidence that β-Ecd protects SH-SY5Y cells against 6-OHDA-induced apoptosis, possibly through mitochondria protection and p53 modulation via ROS-dependent ASK1-p38(MAPK) pathways. The neuroprotective effects of β-Ecd make it a promising candidate as a therapeutic agent for PD.

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Because hepatic fibrosis usually involves more than one pathological process, combination therapy with modalities that target aberrant signaling cascade in activated hepatic stellate cells (HSCs) represents an alternative strategy. This study evaluates the hypothesis that astragaloside IV (AS-IV) and ferulic acid (FA) synergize to inhibit HSCs activation via simultaneous activating nuclear factor erythroid-2-related factor-2 (Nrf2) and blocking transforming growth factor-β (TGF-β) pathways. The combination of FA and AS-IV, hereafter referred to as the AS-IV/FA, at suboptimal concentrations synergistically inhibited HSCs activation, as measured by expressions of α-smooth muscle actin (α-SMA), collagen α type I (Col I) and fibronectin. Nrf2 nuclear accumulation, glutathione (GSH) increase, and reactive oxygen species (ROS) reduction by AS-IV were not potentiated by co-treatment with FA. Similarly, inhibition of TGF-β1 secretion and Smad activity by FA also was not enhanced by combined treatment with AS-IV. AS-IV/FA synergistically suppresses the p38 mitogen-activated protein kinase (MAPK) activity. Inhibition of HSCs activation by AS-IV/FA could be completely blocked by TGF-βs-neutralizing antibody plus shRNA-mediated knockdown of Nrf2. Dual blockade of the TGF-β1/Smad pathway by FA and activation of Nrf2/ARE pathway by AS-IV contributed to the synergistic effects of this combination treatment. These results suggest that combinatorial treatments that target different pathway may afford a more effective strategy to inhibit HSC activation.