Incorporation of T and T contrast material in one nanosystem performing their respective MR contrast role and simultaneously serving as an efficient drug delivery system (DDS) has a significant potential application for clinical diagnosis and chemotherapy of cancer. However, inappropriate incorporation always encountered many issues, such as low contact area of T contrast material with water-proton, inappropriate distance between T contrast material and water molecule, and undesirable disturbance of T contrast material for T imaging. Those issues seriously limited the T or T contrast effect. In this work, we developed a yolk-like FeO@GdO nanoplatform functionalized by polyethylene glycol and folic acid (FA), which could efficiently exert their tumor targeted T-T dual-mode MR imaging and drug delivery role. First, this nanoplatform possessed a high longitudinal relaxation rate (r) (7.91 mM s) and a stronger transverse relaxation rate (r) (386.5 mM s) than that of original FeO (268.1 mM s). Second, cisplatin could be efficiently loaded into this nanoplatform (112 mg/g) and showed pH-responsive release behavior. Third, this nanoplatform could be effectively internalized by HeLa cells with time and dosage dependence. Fourth, the FA receptor-mediated nanoplatform displayed excellent T-T dual mode MR contrast enhancement and anticancer activity both in vitro and in vivo. Fifth, no apparent toxicity for vital organs was observed with systemic delivery of the nanoplatform in vivo. Thus, this nanoplatform could be a potential nanotheranostic for tumor targeted T-T dual-mode MR imaging and chemotherapy.
Microglia, the resident immune cells in the central nervous system, constantly survey the surrounding neural parenchyma and promptly respond to brain injury. Activation of purinergic receptors such as P2Y12 receptors (P2Y12R) in microglia has been implicated in chemotaxis towards ATP that is released by injured neurons and astrocytes. Activation of microglial P2Y12R elicits outward potassium current that is associated with microglial chemotaxis in response to injury. This study aimed at investigating the identity of the potassium channel implicated in microglial P2Y12R-mediated chemotaxis following neuronal injury and understanding the purinergic signaling pathway coupled to the channel. Using a combination of two-photon imaging, electrophysiology and genetic tools, we found the ATP-induced outward current to be largely dependent on P2Y12R activation and mediated by G-proteins. Similarly, P2Y12R-coupled outward current was also evoked in response to laser-induced single neuron injury. This current was abolished in microglia obtained from mice lacking P2Y12R. Dissecting the properties of the P2Y12R-mediated current using a pharmacological approach revealed that both the ATP and neuronal injury-induced outward current in microglia was sensitive to quinine (1 mM) and bupivacaine (400 μM), but not TEA (10 mM) and 4-AP (5 mM). These results suggest that the quinine/bupivacaine-sensitive potassium channels are the functional effectors of the P2Y12R–mediated signaling in microglia activation following neuronal injury.
The processes of angiogenesis and bone formation are coupled both temporally and spatially during bone repair. Bone marrow-derived mesenchymal stem cells (BMSCs) have been effectively used to heal critical-size bone defects.
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