Neuroprotective Effect of Mangiferin against Parkinson's Disease through G-Protein-Coupled Receptor-Interacting Protein 1 (GIT1)-Mediated Antioxidant Defense.

Parkinson's disease (PD), known as a neurodegenerative disease, is characterized by movement disorders, with increasing age being the predominant risk factor for its development. Mangiferin, a bioactive compound isolated from mango, shows potent neuroprotection. In our work, we investigated the neuroprotection and mechanisms of mangiferin against PD. We established PD models by treating SH-SY5Y cells with rotenone and mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and investigated the therapeutic effects of mangiferin. Our results showed that mangiferin exhibited a cell-protective effect. Mangiferin also improved the motor behavior and attenuated the activation of microglia and astrocytes in MPTP mice. In addition, mangiferin decreased reactive oxygen species (ROS) levels and increased glutathione (GSH) and superoxide dismutase (SOD). Mangiferin also markedly activated GIT1, p-ERK, Nrf2, HO-1, and SOD expression and inhibited Keap1 expression in vitro and in vivo. To further investigate the role of GIT1, GIT1 siRNA was used. In the presence of GIT1 siRNA, the neuroprotection of mangiferin in PD was weakened. Our results indicate that mangiferin exhibited its therapeutic effect against PD by regulating GIT1 and its downstream Keap1/Nrf2 pathways. Our studies exhibited that mangiferin showed neuroprotection in PD, and its main target was GIT1. What is more, mangiferin could reduce the oxidative stress of PD by targeting GIT1 and its downstream Keap1/Nrf2 pathways. These indicated that mangiferin is a good candidate for PD therapy. However, the role of p-ERK in mangiferin-treated PD requires further investigation.

Dioscin alleviates lung ischemia/reperfusion injury by regulating FXR-mediated oxidative stress, apoptosis, and inflammation.

Dioscin showed various pharmacological effects in our previous studies; however, the effects and mechanisms against lung ischemia/reperfusion injury (LI/RI) have not been reported. Hypoxia/reoxygenation (H/R) models were established using A549 and primary AEC-II cells, while LI/RI models were established in rats and mice. The effects of dioscin on oxidative stress, inflammation and apoptosis in vivo and in vitro were investigated. The mechanisms were investigated focus on dioscin regulating FXR/LKB1 signaling pathway. Dioscin improved cell viability and mitochondrial membrane potential, reduced reactive oxygen species level, and inhibited H/R-mediated cell apoptosis. It also significantly decreased the lung wet/dry weight ratio, ameliorated levels of oxidative stress indicators, and enhanced the mitochondrial membrane potential and inhibited cell apoptosis in vivo. The results of mechanism research showed that dioscin activated FXR/LKB1 signals by increasing the expression of p-LKB1 and p-AMPKα, promoting the nuclear translocation of Nrf2, up-regulating the levels of HO-1, NQO1 and GCLC, expressed against oxidative stress. Furthermore, dioscin reduced Cyt C released, decreased the expression levels of Caspase-9 and Caspase-3 during apoptosis. Dioscin suppressed inflammation by inhibiting NF-κB translocation, reducing the expression levels of NF-κB, HMGB1, COX-2, IL-1ß, IL-6 and TNF-α. The transfection of FXR or LKB1 siRNA further confirmed that the protective effect of dioscin against LI/RI was attributable to the regulation of FXR/LKB1 signaling pathway. Our research showed that dioscin exhibited potent activity against LI/RI, by adjusting the levels of FXR/LKB1-mediated oxidative stress, apoptosis, and inflammation, and should be considered as a new candidate for treating LI/RI.

Protective effects of dioscin against isoproterenol-induced cardiac hypertrophy via adjusting PKCε/ERK-mediated oxidative stress.

Cardiac hypertrophy (CH) plays a central role in cardiac remodeling and is an independent risk factor for cardiac events. It is imperative to find drugs with protective effect on CH. Dioscin, one natural product, shows various pharmacological activities, and PKCepsilon (PKCε) plays an important role in the physiological hypertrophic responses. Thus, we aimed to investigate the possible protective effect of dioscin on CH through PKCε. In the present study, the isoproterenol (ISO)-induced H9C2 cells and primary cardiomyocytes models, and the ISO-induced rat model were established, and the pharmacodynamics and mechanism of dioscin were investigated. In vitro results prompted that, dioscin significantly improved ISO-induced cardiomyocyte hypertrophy, decreased the levels of cell size, protein content of single cell, reactive oxygen species, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), beta-myosin heavy chain (ß-MHC). Moreover, in vivo, changes in histopathological of the animals caused by ISO are improved by dioscin. And dioscin decreased the index of CH and the levels of CK, MDA, LDH, and increased the levels of GSH, SOD and GSH-Px. Mechanism research showed that dioscin inhibited the expression levels of PKCε, and affected the expression levels of p-MEK, p-ERK, Nrf2, Keap1 and HO-1 to inhibit oxidative stress. In addition, the results of ISO-induced CH in PKCε siRNA transfected H9C2 cells and C57BL/6 mice further showed that the protective effect of dioscin on CH, which was mediated by inhibition of PKCε/ERK signal pathway. In summary, dioscin can effectively inhibit CH by regulating PKCε-mediated oxidative stress, which should be considered as one potent candidate for new drug research and development to treat CH in the future.

Neuroprotective Effect of Dioscin on the Aging Brain.

Our previous works have shown that dioscin, a natural product, has various pharmacological activities, however, its role in brain aging has not been reported. In the present study, in vitro H2O2-treated PC12 cells and in vivo d-galactose-induced aging rat models were used to evaluate the neuroprotective effect of dioscin on brain aging. The results showed that dioscin increased cell viability and protected PC12 cells against oxidative stress through decreasing reactive oxygen species (ROS) and lactate dehydrogenase (LDH) levels. In vivo, dioscin markedly improved the spatial learning ability and memory of aging rats, reduced the protein carbonyl content and aging cell numbers, restored the levels of superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and nitric oxide synthase (NOS) in brain tissue, and reversed the histopathological structure changes of nerve cells. Mechanism studies showed that dioscin markedly adjusted the MAPK and Nrf2/ARE signalling pathways to decrease oxidative stress. Additionally, dioscin also significantly decreased inflammation by inhibiting the mRNA or protein levels of TNF-α, IL-1ß, IL-6, CYP2E1 and HMGB1. Taken together, these results indicate that dioscin showed neuroprotective effect against brain aging via decreasing oxidative stress and inflammation, which should be developed as an efficient candidate in clinical to treat brain aging in the future.