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Ischemic stroke represents the leading cause of adult neurological disability, with no effective therapeutic strategy. Stem cell transplantation promises a new promising for treating stroke, through cell replacement and cytokine paracrine. However, due to the effect of hostile immune microenvironment, the survival and differentiation of stem cells are limited in vivo. Furthermore, the delayed inflammatory response to stroke induced secondary neurological injury. IFN-γ as pro-inflammatory cytokine has the potential to protect stem cell population during inflammatory response, as well as stimulates neurogenesis of stem cells. The purpose of this study was to investigate whether co-injection of neural stem cells and IFN-γ can improve therapeutic outcomes in ischemic stroke model. In this study, we found that IFN-γ did not interfere with the proliferation of neural stem cells (NSCs) in vitro and induced levels of subsequent neuronal differentiation significantly superior to those of other four cytokines BDNF, VEGF, TGF-β, and IGF-1. Co-delivery of IFN-γ (concentration: 50 ng) enhanced the effectiveness of NSC transplantation therapy in ischemic rats. And combined IFN-γ treatment significantly increased neurogenesis in vivo, with more BrdU/DCX dual-positive cells found in ischemic areas. Moreover, co-treatment with IFN-γ and NSCs exerted additional neurological benefits compared with NSC transplantation alone. In conclusion, low concentration of IFN-γ can promote the functions of transplanted NSCs and facilitate their ability of neurological repair. Thus, our findings suggest that co-delivery of NSCs and IFN-γ without genetic modification may be an effective, simple, and novel approach for the treatment of ischemic stroke.

Inflammatory response generated by ischemic stroke commonly affects functional or structural recovery. The aim of this study was to examine the IFN-γ caused inflammatory effects on NSCs in vitro and in vivo. We found that IFN-γ did not affect NSCs proliferation but increased the SOD2 level of inflammatory oxidative stress in NSCs culturing. High dose IFN-γ (500 ng) injection aggravated the level of inflammation in the cerebral ischemic model but did not alter the repairing functions of the NSCs in vivo. NSCs based treatment, including the NSCs-IFN-γ combined treatment, significantly improved the ischemic microenvironment by decreasing CD4+, CD8+ T cells and microglia infiltration. Furthermore, anti-inflammatory cytokines IL-10 and TGF-β1 expression were increased in the NSCs and combined treatment groups, but the level of pro-inflammatory cytokines (IL-1 β, IL-6, IFN-γ, and TNF-α) were decreased. The IFN-γ/Stat1 signaling pathway was also activated. NSCs transplantation therefore promoted the neurological recovery of ischemic stroke rats mainly by altering the inflammatory microenvironment, neutralizing the negative effect of IFN-γ. In conclusion, in addition to promoting cell replacement or engraftment, the NSCs-based transplantation also enhanced the therapeutic effects of transplantation by optimizing its immune microenvironment of ischemic areas.

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The results indicated that the method was well validated and could be practically used for the analysis and evaluation of bus stop safety in China. The proposed model was relatively easy to implement without the requirement of traffic crash data and/or traffic conflict data. In addition, with the proposed method, it was feasible to evaluate countermeasures to improve bus stop safety (e.g., exclusive bus lanes).

Cortex Fraxini is an important traditional Chinese herbal medicine used for the treatment of gout and hyperuricemia. An efficient and rapid ultra-performance liquid chromatography mass spectrometry method was developed and validated for simultaneous quantitation of six coumarins (aesculin, fraxin, aesculetin, fraxetin, sopoletin and 7-hydroxycoumarin) in normal and hyperuricemic rats plasma after oral administration of Cortex Fraxini. The method could successfully be applied for pharmacokinetics studies. The pharmacokinetic behavior of six coumarins in normal and hyperuricemia rats plasma was determined. Results showed that, for some of analytes, the pharmacokinetic parameters (AUC , AUC , C , T and CL) were significantly different between normal and hyperuricemic rats. The different pharmacokinetic parameters might result from renal impairment or a change of metabolic enzymes in the pathological state. The pharmacokinetic study in pathological state could provide more useful information to guide the clinical use of traditional Chinese herbal medicine.

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