Salidroside is being investigated for its therapeutic potential in stroke because it is neuroprotective over an extended therapeutic window of time. In the present study, we investigated the mechanisms underlying the anti-inflammatory effects of salidroside (50 mg/kg intraperitoneally) in rats, given 1 h after reperfusion of a middle cerebral artery that had been occluded for 2 h. After 24 h, we found that salidroside increased the neuronal nuclear protein NeuN and reduced the marker of microglia and macrophages CD11b in the peri-infarct area of the brain. Salidroside also decreased IL-6, IL-1β, TNF-α, CD14, CD44, and iNOs mRNAs. At the same time, salidroside increased the ratio of phosphorylated protein kinase B (p-Akt) to total Akt. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 prevented this increase in p-Akt and reversed the inhibitory effects of salidroside on CD11b and inflammatory mediators. Salidroside also elevated the protein levels of hypoxia-inducible factor (HIF) subunits HIF1α, HIF2α, HIF3α, and of erythropoietin (EPO). The stimulatory effects of salidroside on HIFα subunits were blocked by LY294002. Moreover, YC-1, a HIF inhibitor, abolished salidroside-mediated increase of HIF1α and prevented the inhibitory effects of salidroside on CD11b and inflammatory mediators. Taken together, our results provide evidence for the first time that all three HIFα subunits and EPO can be regulated by PI3K/Akt in cerebral tissue, and that salidroside entrains this signaling pathway to induce production of HIFα subunits and EPO, one or more of which mediate the anti-inflammatory effects of salidroside after cerebral IRI.

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BackgroundLung cancer is the primary cause of cancer-related death worldwide. A redox-sensitive nanocarrier system was developed for tumor-targeted drug delivery and sufficient drug release of the chemotherapeutic agent paclitaxel (PTX) for improved lung cancer treatment.MethodsThe redox-sensitive nanocarrier system constructed from a hyaluronic acid-disulfide-vitamin E succinate (HA-SS-VES, HSV) conjugate was synthesized and PTX was loaded in the delivery system. The physicochemical properties of the HSV nanoparticles were characterized. The redox-sensitivity, tumor-targeting and intracellular drug release capability of the HSV nanoparticles were evaluated. Furthermore, in vitro and in vivo antitumor activity of the PTX-loaded HSV nanoparticles was investigated in a CD44 over-expressed A549 tumor model.ResultsThis HSV conjugate was successfully synthesized and self-assembled to form nanoparticles in aqueous condition with a low critical micelle concentration of 36.3 μg mL−1. Free PTX was successfully entrapped into the HSV nanoparticles with a high drug loading of 33.5% (w/w) and an entrapment efficiency of 90.6%. Moreover, the redox-sensitivity of the HSV nanoparticles was confirmed by particle size change of the nanoparticles along with in vitro release profiles in different reducing environment. In addition, the HA-receptor mediated endocytosis and the potency of redox-sensitivity for intracellular drug delivery were further verified by flow cytometry and confocal laser scanning microscopic analysis. The antitumor activity results showed that compared to redox-insensitive nanoparticles and Taxol®, PTX-loaded redox-sensitive nanoparticles exhibited much greater in vitro cytotoxicity and apoptosis-inducing ability against CD44 over-expressed A549 tumor cells. In vivo, the PTX-loaded HSV nanoparticles possessed much higher antitumor efficacy in an A549 mouse xenograft model and demonstrated improved safety profile. In summary, our PTX-loaded redox-sensitive HSV nanoparticles demonstrated enhanced antitumor efficacy and improved safety of PTX.ConclusionThe results of our study indicated the redox-sensitive HSV nanoparticle was a promising nanocarrier for lung cancer therapy.

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Salidroside exhibits anti-inflammatory, anti-oxidative, and anti-apoptotic properties. To identify whether salidroside might be a candidate for treating ischemic stroke, we investigated the effects of salidroside or vehicle, given daily for 6 days, after middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for either 1 or 48 h in rats. Salidroside reduced cerebral infarct volume and significantly improved neurological scores whether started after 1 or 48 h of reperfusion. Microarray analysis showed that 20 % (133/678) of the genes down-regulated by ischemia and 1 h of reperfusion were up-regulated by salidroside, whereas 13 % (105/829) of the genes induced by ischemia-reperfusion were inhibited by salidroside, suggesting that salidroside can reverse effects of ischemia-reperfusion on gene expression. The main enriched functional categories induced by salidroside were genes related to synaptic plasticity, whereas salidroside inhibited genes related to inflammation. Induction of Egr1, Egr2, Egr4, and Arc by salidroside was confirmed by qRT-PCR and western blotting in ischemic brains treated after either 1 or 48 h of reperfusion. The potential protective role of Egr4 in salidroside-mediated neuroprotection was subsequently investigated in CoCl2-treated PC12 cells. Egr4 was dose-dependently induced by salidroside in PC12 cells, and depleting Egr4 with target-specific siRNA increased caspase-3 activity and Bax, but decreased Bcl-xl, which were reversed by salidroside. Finally, we confirmed that salidroside inhibited the Bax/Bcl-xl-related apoptosis after MCAO with reperfusion. In conclusion, salidroside is highly neuroprotective with a wide therapeutic time window after ischemia-reperfusion injury in the rat, and this partially involves induction of Egrs, leading to inhibition of Bax/Bcl-xl-related apoptosis.

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Salidroside is neuroprotective across a wide therapeutic time-window after cerebral ischemia-reperfusion injury (IRI). Here, we investigated the role of complement in mediating effects of salidroside after cerebral IRI in rats. Rats were administrated with vehicle or salidroside 50 mg/kg, given daily for either 24 or 48 h, after middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for 1 h. Levels of proteins in ischemic brain were measured by immunofluorescence and western blotting. We observed early increases in the deposition of immunoglobulin M, mannose-binding lectin 2, and annexin IV on cerebral endothelial cells, induction of the complement components C3 and C3a, by 24 h after IRI, and a later significant increase in the complement component C1q by 48 h. Salidroside prevented these changes. The neuroplasticity-related early growth response proteins Egr1, Egr2, and Egr4 and activity-regulated cytoskeleton-associated protein increased transiently in the first 6 h after IRI but then decreased below baseline by 48 h after IRI. Neither salidroside nor a C3a receptor antagonist (C3aRA) affected these proteins 24 h after IRI, but both reversed their later decreases to similar and non-additive extents. Salidroside and C3aRA increased NeuN in a non-additive manner after IRI. Our results suggest that salidroside exerts neuroprotection by reducing early activation of the lectin pathway on the cerebral endothelium and inhibiting the gradual activation of the classical pathway after cerebral IRI. This prolonged neuroprotection may depend, at least in part, on increased expression of neuroplasticity-related genes driven by reduced complement activation.

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