Scavenging reactive oxygen species (ROS) by antioxidants is the important therapy to cerebral ischemia-reperfusion injury (CIRI) in stroke. The antioxidant with novel dual-antioxidant mechanism of directly scavenging ROS and indirectly through antioxidant pathway activation may be a promising CIRI therapeutic strategy. In our study, a series of chalcone analogues were designed and synthesized, and multiple potential chalcone analogues with dual antioxidant mechanisms were screened. Among these compounds, the most active
33
not only conferred cytoprotection of H
2
O
2
-induced oxidative damage in PC12 cells through scavenging free radicals directly and activating NRF2/ARE antioxidant pathway at the same time, but also played an important role against ischemia/reperfusion-related brain injury in animals. More importantly, in comparison with mono-antioxidant mechanism compounds,
33
exhibited higher cytoprotective and neuroprotective potential
in vitro
and
in vivo.
Overall, our findings showed compound
33
could emerge as a promising anti-ischemic stroke drug candidate and provided novel dual-antioxidant mechanism strategies and concepts for oxidative stress-related diseases treatment.
Chalcone derivatives (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(4-methoxyphenyl) prop-2-en-1-one and (E)-3-(4-hydroxyphenyl)-1-(4-methoxyphenyl) prop-2-en-1-one (Compounds 1 and 2) have been demonstrated to be potent anti-inflammatory agents in our previous study. In light of the relationship of intracellular mechanisms between anti-inflammatories and antioxidants, we further designed and synthesized a series of chalcone derivatives based on 1 and 2, to explore their antioxidant efficacy. The majority of the derivatives exhibited strong protective effects on PC12 (PC12 rat pheochromocytoma) cells exposed to H2O2, and all compounds were nontoxic. A preliminary structure-activity relationship was proposed. Compounds 1 and 1d ((E)-2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl) phenyl acrylate) exerted the action in a good dose-dependent manner. Quantitative RT-PCR (qRT-PCR) and western blot analysis showed that 1 and 1d significantly improve the expression of nuclear factor erythroid 2 p45-related factor 2 (Nrf2)-dependent antioxidant genes g-Glutamylcysteine Ligase Catalytic Subunit (GCLC) and heme oxygenase-1 (HO-1) and their corresponding proteins (γ-glutamyl cysteine synthase (γ-GCS) and HO-1) in PC12 cells. Inhibition of GCLC and HO-1 by specific inhibitors, l-buthionine-S-sulfoximine (BSO) and zinc protoporphyrin (ZnPP), respectively, partially reduce the protective effect of 1 and 1d. These data present a series of novel chalcone analogs, especially compounds 1 and 1d, as candidates for treating oxidative stress-related disease by activating the Nrf2-antioxidant responsive element (ARE) pathway.
High performance liquid chromatography coupled with microdialysis sampling and electrochemical detection (HPLC-ECD) has been used to determine dopamine (DA). In the HPLC-ECD a multi-wall carbon nanotube electrode chemically modified with carboxyl groups (MWNT-COOH CME) was used as the working electrode for determination of DA. The results indicated that the MWNT-COOH CME enabled efficient electrocatalytic oxidation of DA with relatively high sensitivity and stability and long life. Peak currents for dopamine were linearly dependent on concentration in the range 5.0 x 10(-9) to 5.0 x 10(-5) mol L(-1) and the calculated detection limit (S/N=3) was 2.5 x 10(-9) mol L(-1). The method had been successfully used to measure dopamine in rat striatal microdialysate. To study the physiological effect of nitric oxide (NO) on striatal release of DA, 0.5 mmol L(-1) sodium nitroprusside (SNP) was a continuously perfused into rat striatum. This resulted in a 46% increase in DA basal level.
Four new steroids, named 7-dehydroerectasteroid F (1), 11α-acetoxyarmatinol A (2), 22,23-didehydroarmatinol A (3), and 3-O-acetylhyrtiosterol (4), together with 11 previously described analogues, were isolated from a South China Sea collection of the soft coral Dendronephthya gigantea. The structures of the new steroids were elucidated by comprehensive spectroscopic analysis and by comparison with previously reported data. Compound 1 showed potent protection against H 2 O 2 -induced oxidative damage in neuron-like PC12 cells by promoting nuclear translocation of Nrf2 and enhancing the expression of HO-1. 1 represents the first steroid-type antioxidant from marine organisms.
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