A simple, efficient, and general method has been developed for the synthesis of various α-aminophosphonate derivatives 4a-4l by treatment of substituted benzaldehydes and aniline with bis(2-methoxyethyl)-or bis(2-ethoxyethyl) phosphite under microwave irradiation without solvents and catalysts. The products were characterized by elemental analysis, IR, 1 H-NMR, 13 C-and 31 P-NMR spectra. The X-ray crystallographic data of the representative compound 4l was determined. The new α-aminophosphonate derivatives were found to possess moderate to good antiviral activity.

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Emerging evidence reveals that an aberrant accumulation of b-amyloid (Ab) is the main reason of Alzheimer's disease (AD) pathogenesis. Thus, inhibition of Ab-induced neurotoxicity may be promising therapeutic tactics to mitigate AD onset and advance. The development of agent candidates by cultured neurons against Ab-induced cytotoxicity is widely accepted to be an efficient strategy to explore the drug for AD patients. Previously, we have revealed that trilobatin (TLB), a small molecule monomer, derives from Lithocarpus polystachyus Rehd, possessed antioxidative activities on hydrogen peroxide-induced oxidative injury in PC12 cells. The present study was designed to investigate the effects and the underlying mechanism of TLB on Abinduced injury in hippocampal HT22 cells. The results demonstrated that TLB attenuated Ab 25-35 -induced HT22 cell death, as evidenced by MTT assay and LDH release. Furthermore, TLB dramatically mitigated cell death after Ab 25-35 insulted via decreasing the intracellular and mitochondrial ROS overproduction and restoring antioxidant enzyme activities, as well as suppressing apoptosis. Of note, Ab 25-35 triggered increase in ratio of Bax/Bcl-2, activation of caspase-3, phosphorylation of tau, JNK, p38 MAPK, and decrease in Sirt3 expression, whereas TLB reversed these changes. Intriguingly, TLB could directly bind to p38, as evidenced by molecular docking and p38 inhibitor. Taken together, the results reveal that TLB effectively protects against Ab 25-35 -induced neuronal cell death via activating ROS/p38/caspase 3-dependent pathway. Our findings afford evidence for the potential development of TLB to hinder neuronal death during AD.

Nrf2-mediated oxidative stress is a promising target of exhaustive exercise-induced fatigue (EEIF). Trilobatin (TLB) is a naturally occurring food additive with antioxidant effect and Nrf2 activation potency. The present study aimed to investigate the effect of TLB on EEIF and elucidate its underlying mechanism. Our results showed that TLB exerted potent anti-EEIF effect, as reflected by the rope climbing test and exhaustive swimming test. Moreover, TLB also effectively reduced the levels of lactate, creatine kinase, and blood urea nitrogen, and increased liver glycogen and skeletal muscle glycogen in mice after EEIF insult. Additionally, TLB also balanced the redox status as evidenced by decreasing the generation of reactive oxygen species and improving the antioxidant enzyme activities including superoxide dismutase, catalase, and glutathione peroxidase, as well as the level of glutathione both in the tissue of muscle and myocardium. Furthermore, TLB promoted nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus, and upregulated its downstream antioxidant response element (ARE) including quinone oxidoreductase-1 and heme oxygenase-1. Intriguingly, TLB also upregulated the GPx4 protein expression and reduced iron overload in mice after EEIF insult. Encouragingly, the beneficial effect of TLB on EEIF-induced oxidative stress and ferroptosis were substantially abolished in Nrf2-deficient mice. In conclusion, our findings demonstrate, for the first time, that TLB alleviates EEIF-induced oxidative stress through mediating Nrf2/ARE/ferroptosis axis.

Icariside II (ICS II), a phosphodiesterase 5 inhibitor (PDE 5-I), is a major ingredient of Epimedium brevicornum, with wide spectrum of neuroprotective properties. However, little is known about the potential beneficial effect of ICS II on neuronal cell proliferation, and its possible underlying mechanism remains still unclear. We hypothesized that the beneficial effect of ICS II on neuron-like highly differentiated rat pheochromocytoma (PC12) cell proliferation is correlated with the nitric oxide (NO) signaling pathway and its upstream of PI3K/AKT pathway. PC12 cells were treated with ICS II alone or together with L-NMMA, H89, KT-5823, and/or LY294002 (the inhibitor of NOS, PKA, PKG, PI3K, respectively). It was found that ICS II concentration-dependently promoted PC12 cells proliferation, and cell cycle analysis showed that the proportion of ICS II-treated PC12 cells in S phase was higher than that of control. Moreover, ICS II at the appropriate concentration (100 μM) not only increased nNOS expression, NO production, but also enhanced cGMP content and PKG activity. The addition of L-NMMA and KT-5 823 significantly inhibited the effects of ICS II on nNOS expression, NO production and PKG activity. Furthermore, LY294002 significantly decreased p-AKT level, NOS activity, NO production and nNOS expression, but it did not affect iNOS expression. These findings demonstrate that the beneficial effect of ICS II on neuronal cell proliferation, and its possible underlying mechanisms are, at least partly, through activating AKT/nNOS/NO/cGMP/PKG signaling pathway.

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Lithocarpus polystachyus Rehd. (sweet tea; ST) leaves is a type of chinese folkloric medicine from southern china. The purpose of the present study was to explore the neuroprotective effect of ST, and to explore its underlying mechanisms in hydrogen peroxide (H 2 O 2)-induced neuronal cell injury in cultured human neuroblastoma. H 2 O 2 was used as oxidant inducer and human SH-SY5Y neuroblastoma cells were treated with various concentrations of ST. cell viability and cell death were detected using MTT and LdH assays, respectively. Additionally, the production of intracellular and mitochondrial reactive oxygen species (ROS) were determined by 2' ,7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSOX Red, respectively. The production of malondialdehyde (MdA), reduced glutathione (GSH) level, glutathione peroxidase (GSH-Px), superoxide dismutase (SOd) activities, and NAd + /NADH ratio were confirmed using relevant kits. The expression of adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor coactivator (PGc)-1α, Sirt3, isocitrate dehydrogenase (IdH)2, forkhead boxO3a (Foxo3a), and SOd2 were analyzed by western blot analysis. It was demonstrated that pre-treatment with ST enhanced cell viability and repressed cell death, and it also reduced intracellular and mitochondrial ROS accumulation. Additionally, ST attenuated MdA production and enhanced GSH level, GSH-Px and SOd activities. Furthermore, ST not only increased NAd + /NAdH ratio, but also inhibited the decrease of AMPK, PGc-1α, Sirt3, IdH2, Foxo3a, and SOd2. The present study revealed that ST exerts protective effects against oxidative stress-induced SH-SY5Y cells injury, and the underlying mechanisms are, at least partly, associated with its antioxidant capacity and function through mitochondrial Sirt3 signaling pathway.

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