Near infrared (NIR)-emitting persistent luminescent nanoparticles (PLNPs) have great potential for in vivo bioimaging with the advantages of no need for in situ excitation, high signal-to-noise ratio, and deep tissue penetration. However, functional NIR-emitting PLNPs with long afterglow for long-term in vivo imaging are lacking. Here, we show the synthesis of NIR-emitting long-persistent luminescent nanoparticles (LPLNPs) Zn2.94Ga1.96Ge2O10:Cr(3+),Pr(3+) by a citrate sol-gel method in combination with a subsequent reducing atmosphere-free calcination. The persistent luminescence of the LPLNPs is significantly improved via codoping Pr(3+)/Cr(3+) and creating suitable Zn deficiency in zinc gallogermanate. The LPLNP powder exhibits bright NIR luminescence in the biological transparency window with a superlong afterglow time of over 15 days. A persistent energy transfer between host and Cr(3+) ion in the LPLNPs is observed and its mechanism is discussed. PEGylation greatly improves the biocompatibility and water solubility of the LPLNPs. Further bioconjugation with c(RGDyK) peptide makes the LPLNPs promising for long-term in vivo targeted tumor imaging with low toxicity.

Mesenchymal stem cell (MSC)-derived exosomes have been recognized as new candidates for cell-free treatment of various diseases. However, maintaining the retention and stability of exosomes over time in vivo after transplantation is a major challenge in the clinical application of MSC-derived exosomes. Here, we investigated if human placenta-derived MSC-derived exosomes incorporated with chitosan hydrogel could boost the retention and stability of exosomes and further enhance their therapeutic effects. Our results demonstrated that chitosan hydrogel notably increased the stability of proteins and microRNAs in exosomes, as well as augmented the retention of exosomes in vivo as confirmed by Gaussia luciferase imaging. In addition, we assessed endothelium-protective and proangiogenesis abilities of hydrogel-incorporated exosomes in vitro. Meanwhile, we evaluated the therapeutic function of hydrogel-incorporated exosomes in a murine model of hindlimb ischemia. Our data demonstrated that chitosan hydrogel could enhance the retention and stability of exosomes and further augment the therapeutic effects for hindlimb ischemia as revealed by firefly luciferase imaging of angiogenesis. The strategy used in this study may facilitate the development of easy and effective approaches for assessing and enhancing the therapeutic effects of stem cell-derived exosomes.

This work was supported by MOST of China National Basic Research Program (grant number: 2010CB94500 and 2012CB911200). The authors have no competing interests to declare.

The yeast Candida albicans is an opportunistic pathogen that threatens patients with compromised immune systems. Immune cell defenses against C. albicans are complex but typically involve the production of reactive oxygen species and nitrogen radicals such as nitric oxide (NO) that damage the yeast or inhibit its growth. Whether Candida defends itself against NO and the molecules responsible for this defense have yet to be determined. The defense against NO in various bacteria and the yeast Saccharomyces cerevisiae involves an NO-scavenging flavohemoglobin. The C. albicans genome contains three genes encoding flavohemoglobinrelated proteins, CaYHB1, CaYHB4, and CaYHB5. To assess their roles in NO metabolism, we constructed strains lacking each of these genes and demonstrated that just one, CaYHB1, is responsible for NO consumption and detoxification. In C. albicans, NO metabolic activity and CaYHB1 mRNA levels are rapidly induced by NO and NO-generating agents. Loss of CaYHB1 increases the sensitivity of C. albicans to NO-mediated growth inhibition. In mice, infections with Candida strains lacking CaYHB1 still resulted in lethality, but virulence was decreased compared to that in wild-type strains. Thus, C. albicans possesses a rapid, specific, and highly inducible NO defense mechanism involving one of three putative flavohemoglobin genes.The dimorphic fungus Candida albicans causes infections in immunocompromised hosts and is particularly problematic for AIDS and cancer patients. In healthy individuals, phagocytic immune cells such as macrophages (17), monocytes (37, 45), and neutrophils (45) defend against Candida infections by producing several growth inhibitors and cytotoxic compounds, including microbicidal enzymes (41) and reactive oxygen and nitrogen species (50). One potentially powerful weapon against C. albicans is nitric oxide (NO). Macrophages produce high concentrations of this free radical via the action of an inducible NO synthase (36), inhibition of which strongly decreases the candidacidal activity of macrophages (4,15,43). Despite the increasing understanding of host immune defenses mounted against this opportunistic pathogen, the means by which C. albicans resists NO or other microbicidal agents is not well understood.Microbes protect themselves against NO toxicity by using enzymes that convert NO to less toxic molecules. Flavohemoglobin, an NO dioxygenase (NOD) that converts NO to nitrate (26,29,55), is found in bacteria and yeasts (7,58). This enzyme is encoded by a single gene in several different organisms: for example, by hmp in Escherichia coli (49) and by ScYHB1 in Saccharomyces cerevisiae (57). Flavohemoglobin is necessary for virulence of a plant pathogen, the bacterium Erwinia chrysanthemi (18). hmp-negative bacteria are more easily inhibited by 21,26,38), and expression of hmp is strongly induced by NO (8,42). Hmp induction by NO is mediated by a derepression mechanism in which NO inactivates a metal-binding transcription factor, Fnr (10, 42) or Fur (8, 11). In the yeast S. cerevisi...

amount of ascites and improved intestinal motility in cirrhotic rats, which may be associated with its effect on ascites and was involved in the mechanisms regulating the SCF/c-kit signaling pathway in ICCs and improving gastrointestinal hormone secretion.

Low cell retention and engraftment after transplantation limit the successful application of stem cell therapy for AKI. Engineered microenvironments consisting of a hydrogel matrix and growth factors have been increasingly successful in controlling stem cell fate by mimicking native stem cell niche components. Here, we synthesized a bioactive hydrogel by immobilizing the C domain peptide of IGF-1 (IGF-1C) on chitosan, and we hypothesized that this hydrogel could provide a favorable niche for adipose-derived mesenchymal stem cells (ADSCs) and thereby enhance cell survival in an AKI model. In vitro studies demonstrated that compared with no hydrogel or chitosan hydrogel only, the chitosan-IGF-1C hydrogel increased cell viability through paracrine effects. In vivo, cotransplantation of the chitosan-IGF-1C hydrogel and ADSCs in ischemic kidneys ameliorated renal function, likely by the observed promotion of stem cell survival and angiogenesis, as visualized by bioluminescence imaging and attenuation of fibrosis. In conclusion, IGF-1C immobilized on a chitosan hydrogel provides an artificial microenvironment for ADSCs and may be a promising therapeutic approach for AKI.

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The development of multimodal nanoprobes that combined properties of near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI) within a single probe is very important for medical diagnosis. The NIR-emitting persistent luminescent nanoparticles (PLNPs) are ideal for optical imaging owing to no need for in situ excitation, the absence of background noise, and deep tissue penetration. However, no PLNP based multimodal nanoprobes have been reported so far. Here, we report a novel multimodal nanoprobe based on the gadolinium complexes functionalized PLNPs (Gd(III)-PLNPs) for in vivo MRI and NIR luminescence imaging. The Gd(III)-PLNPs not only exhibit a relatively higher longitudinal relaxivity over the commercial Gd(III)-diethylenetriamine pentaacetic acid complexes but also keep the superlong persistent luminescence. The prepared Gd(III)-PLNPs multimodal nanoprobe offers great potential for MRI/optical imaging in vivo.