In vitro hypoxic preconditioning (HP) of mesenchymal stem cells (MSCs) could ameliorate their viability and tissue repair capabilities after transplantation into the injured tissue through yet undefined mechanisms. There is also experimental evidence that HP enhances the expression of both stromal-derived factor-1 (SDF-1) receptors, CXCR4 and CXCR7, which are involved in migration and survival of MSCs in vitro, but little is known about their role in the in vivo therapeutic effectiveness of MSCs in renal ischemia/reperfusion (I/R) injury. Here, we evaluated the role of SDF-1-CXCR4/CXCR7 pathway in regulating chemotaxis, viability and paracrine actions of HP-MSCs in vitro and in vivo. Compared with normoxic preconditioning (NP), HP not only improved MSC chemotaxis and viability but also stimulated secretion of proangiogenic and mitogenic factors. Importantly, both CXCR4 and CXCR7 were required for the production of paracrine factors by HP-MSCs though the former was only responsible for chemotaxis while the latter was for viability. SDF-1α expression was upregulated in postischemic kidneys. After 24 h systemical administration following I/R, HP-MSCs but not NP-MSCs were selectively recruited to ischemic kidneys and this improved recruitment was abolished by neutralization of CXCR4, but not CXCR7. Furthermore, the increased recruitment of HP-MSCs was associated with enhanced functional recovery, accelerated mitogenic response, and reduced apoptotic cell death. In addition, neutralization of either CXCR4 or CXCR7 impaired the improved therapeutic potential of HP-MSCs. These results advance our knowledge about SDF-1-CXCR4/CXCR7 axis as an attractive target pathway for improving the beneficial effects of MSC-based therapies for renal I/R.

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effect), a lower pH value, as well as a high level of oxidative stress. [4-9] Especially, the overproduction of reactive oxygen species (ROS) induces a serious oxidative stress, which is strongly implicated to various tumors. [8,9] In addition, a high ROS level is also considered to be an endpoint of the alteration of several important metabolic pathways in tumors. [8-11] Thus, modulation of the intratumor ROS level, either by scavenging ROS or increasing ROS, is a promising approach to anticancer therapy and ROS-related biomedical fields. [10-19] Recently, nanomaterial-enabled biocatalytic chemodynamic therapy has been demonstrated as a promising method for therapeutic intervention in a variety of tumors. [11-16,20] Through this biocatalytic tumor therapy, intratumor H 2 O 2 can be converted into toxic hydroxyl radicals (• OH) with the help of catalysts that can then induce tumor cell apoptosis and death through oxidative damage to various biomacromolecules, including DNA, lipids, and proteins. Nevertheless, the relatively deficient intratumoral H 2 O 2 level significantly lowers the biocatalytic therapeutic efficiency. [21-27] Thus, the focus has been on increasing the intratumoral H 2 O 2 level through oxidization of intratumoral molecules Catalytic generation of reactive oxygen species has been developed as a promising methodology for tumor therapy. Direct O 2 •− production from intratumor oxygen exhibits exceptional tumor therapeutic efficacy. Herein, this therapy strategy is demonstrated by a pH-responsive hybrid of porous CeO 2 nanorods and sodium polystyrene sulfonate that delivers high oxidative activity for O 2 •− generation within acidic tumor microenvironments for chemodynamic therapy and only limited oxidative activity in neutral media to limit damage to healthy organs. The hydrated polymer-nanorod hybrids with large hydrodynamic diameters form nanoreactors that locally trap oxygen and biological substrates inside and improve the charge transfer between the catalysts and substrates in the tumor microenvironment, leading to enhanced catalytic O 2 •− production and consequent oxidation. Together with successful in vitro and in vivo experiments, these data show that the use of hybrids provides a compelling opportunity for the delivery selective chemodynamic tumor therapy.

Oxidative stress and inflammation are involved in the pathogenesis in renal ischemia/reperfusion (I/R) injury. It has been demonstrated that polydatin processed the antioxidative, anti-inflammatory, and nephroprotective properties. However, whether it has beneficial effects and the possible mechanisms on renal I/R injury remain unclear. In our present study I/R models were simulated both in vitro and in vivo. Compared with vehicle control, the administration of polydatin significantly improved the renal function, accelerated the mitogenic response and reduced cell apoptosis in renal I/R injury models, strongly suppressed the I/R-induced upregulation of the expression of tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, inducible nitric oxide synthase, prostaglandin E-2, and nitric oxide levels, and dramatically decreased contents of malondialdehyde, but it increased the activity of superoxide dismutase, glutathione transferase, glutathione peroxidase and catalase, and the level of glutathione. Further investigation showed that polydatin upregulated the phosphorylation of Akt in kidneys of I/R injury dose-dependently. However, all beneficial effects of polydatin mentioned above were counteracted when we inhibited PI3K/Akt pathway with its specific inhibitor, wortmannin. Taken together, the present findings provide the first evidence demonstrating that PD exhibited prominent nephroprotective effects against renal I/R injury by antioxidative stress and inflammation through PI3-K/Akt-dependent molecular mechanisms.