Targeted Delivery of Curcumin Rescues Endoplasmic Reticulum-Retained Mutant NOX2 Protein and Avoids Leukocyte Apoptosis.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by defects in the leukocyte NADP oxidase. We previously reported that sarcoplasmic/endoplasmic reticulum calcium pump (SERCA) inhibitors could be used to rescue mutant H338Y-gp91phox protein of a particular type of CGD with a CybbC1024T mutation, leading to endoplasmic reticulum (ER) retention of the mutant protein. In this study, we developed a novel mouse model with the CybbC1024T mutation on a Cybb knockout background and investigated the therapeutic effects of ER-targeted delivery of the SERCA inhibitor, curcumin, with poly(lactic-coglycolic acid) (PLGA) nanoparticles (NPs). We found that PLGA encapsulation improved the efficacy of curcumin as a SERCA inhibitor to induce ER calcium release. ER-targeting curcumin-loaded PLGA NPs reduced and delayed extracellular calcium entry and protected the cells from mitochondrial damage and apoptosis. In vivo studies showed that ER-targeting curcumin-loaded PLGA NPs treatment enhanced neutrophil gp91phox expression, ROS production and peritoneal bacterial clearance ability of the CybbC1024T transgenic Cybb -/- mice. Our findings indicate that ER-targeted delivery of curcumin not only rescues ER-retained H338Y-gp91phox protein, and hence leukocyte function, but also enhances the bioavailability and reduces cytotoxicity. Modulation of ER function by using organelle-targeted NPs may be a promising strategy to improve the therapeutic potential of curcumin as a treatment for CGD.

Quantitative analysis of tissue inflammation and responses to treatment in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and review of literature.

BACKGROUND/PURPOSE: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a severe autoimmune disease that is caused by regulatory T cell deficiency due to FOXP3 gene mutations. The long-term outcome can be variable depending on the extent of tissue damage caused by autoimmunity and infections, the use of immunosuppressive treatment or sequela of bone marrow transplantation. METHODS: We used immunohistochemical staining to analyze cell types infiltrating the tissue of affected organs from a classic IPEX patient with a splicing mutation (c.736-2A>C) in the FOXP3 gene. Expression of transcription factors that are critical for immune responses including T-bet, GATA-3, RORγt, and FOXP3 were evaluated in various tissue samples. For objective analysis of the distribution of different cell types in tissues, we used an automated microscope-based image acquiring system to assess quantitatively the different cell types by investigating the histopathological changes in the patient's biopsy samples obtained from the intestine and the kidneys before and after treatment. RESULTS: The percentages of cells expressing the TH2-associated transcription factor GATA3 were higher in the IPEX patient before treatment than in controls, suggesting that TH2-type cells contribute to the tissue inflammation of the gut and kidneys in IPEX syndrome. Immunosuppressive treatment effectively decreased the number of effector cells in the kidneys and intestine of the IPEX patient. CONCLUSION: This study provides quantitative evidence that the inflamed intestinal and renal tissues of the IPEX patient contain TH2-type immune effector cells, which decreased in number after immunosuppressive treatment was initiated and the clinical symptoms had improved.

Enhanced Particulate Organic Carbon Export at Eddy Edges in the Oligotrophic Western North Pacific Ocean.

Mesoscale eddies in the subtropical oligotrophic ocean are ubiquitous and play an important role in nutrient supply and oceanic primary production. However, it is still unclear whether these mesoscale eddies can efficiently transfer CO2 from the atmosphere to deep waters via biological pump because of the sampling difficulty due to their transient nature. In 2007, particulate organic carbon (POC) fluxes, measured below the euphotic zone at the edge of warm eddy were 136-194 mg-C m-2 d-1 which was greatly elevated over that (POC flux = 26-35 mg-C m-2 d-1) determined in the nutrient-depleted oligotrophic waters in the Western North Pacific (WNP). In 2010, higher POC fluxes (83-115 mg-C m-2 d-1) were also observed at the boundary of mesoscale eddies in the WNP. The enhanced POC flux at the edge of eddies was mainly attributed to both large denuded diatom frustules and zooplankton fecal pellets based on scanning electron microscopy (SEM) examination. The result suggests that mesoscale eddies in the oligotrophic waters in the subtropical WNP can efficiently increase the oceanic carbon export flux and the eddy edge is a crucial conduit in carbon sequestration to deep waters.