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Photodynamic therapy (PDT) represents an attractive promising route for melanoma treatment. However, its therapeutic efficacy is compromised by inefficient drug delivery and high glutathione (GSH) levels in cancer cells. To overcome these challenges, microneedles (MNs) system loaded with GSH-scavenging nanocomposites was presented for nitric oxide (NO) enhanced PDT. The nanocomposites consisted of S-nitroso-N-acrylate penicillamine (SNAP; a NO donor) grafted fourth-generation polyamide amine dendrimer (G4) and chlorin e6 (Ce6). Upon local insertion of polyvinylpyrrolidone MNs, G4-SNAP/Ce6 composites were fast delivered and significantly amplified the therapeutic effects during PDT, via GSH depletion and reactive nitrogen species generation. Even with a single administration and low power light exposure, MNs with G4-SNAP/Ce6 effectively halt the tumor progression. The system demonstrated better cancer ablation efficacy than Ce6 alone toward melanoma. The strategy may inspire new ideas for future PDT-related therapy for skin tumors. [ABSTRACT FROM AUTHOR]

We study the effect of particle losses on dynamical phase diffusion in a two-mode Bose-Einstein condensate. Starting with an equal-population coherent state, the single-particle coherence is solved analytically by the Monte Carlo wave function method. We show that decoherence slows down the loss of single-particle coherence. Moreover, we find that the bigger phase diffusion is, the more sensitive to the noise it becomes. Finally, we discuss the effect of the losses on the spin squeezing and show that the squeezing angle is robust to the decoherence even though the value of the squeezing is greatly affected. [ABSTRACT FROM AUTHOR]

Osteopontin is a multifunctional matricellular protein abundantly expressed during inflammation and repair. Osteopontin deficiency is associated with abnormal wound repair characterized by aberrant collagen fibrillogenesis in the heart and skin. Recent gene microarray studies found that osteopontin is abundantly expressed in both human and mouse lung fibrosis. Macrophages and T cells are known to be major sources of osteopontin. During lung fibrosis, however, osteopontin expression continues to increase when inflammation has receded, suggesting alternative sources of ostepontin during this response. In this study, we demonstrate immunoreactivity for osteopontin in lung epithelial and inflammatory cells in human usual interstitial pneumonitis and murine bleomycin-induced lung fibrosis. After treatment with bleomycin, osteopontin-null mice develop lung fibrosis characterized by dilated distal air spaces and reduced type I collagen expression compared with wild-type controls. There is also a significant decrease in levels of active transforming growth factor-β1 and matrix metalloproteinase-2 in osteopontin null mice. Type III collagen expression and total collagenase activity are similar in both groups. These results demonstrate that osteopontin expression is associated with important fibrogenic signals in the lung and that the epithelium may be an important source of osteopontin during lung fibrosis. [ABSTRACT FROM AUTHOR]

The cyclooxygenase (COX) metabolite, 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2), has been reported to inhibit the expression of a number of genes involved in the pathogenesis of arthritis. However, its effects on COX‐2 remain controversial. We undertook this study to investigate the effects of 15d‐PGJ2 on interleukin‐1β (IL‐1β)–induced COX‐2 expression in human synovial fibroblasts (HSFs).HSFs were cultured with IL‐1β in the absence or presence of 15d‐PGJ2, and the levels of COX‐2 protein and messenger RNA (mRNA) expression were evaluated using Western blotting and real‐time reverse transcriptase–polymerase chain reaction, respectively. COX‐2 promoter activity was analyzed in transient transfection experiments. Chromatin immunoprecipitation assays were performed to evaluate the level of histone acetylation and the recruitment of histone deacetylases (HDACs) 1, 2, and 3 and histone acetylase (HAT) p300 to the COX‐2 promoter.IL‐1β–induced COX‐2 protein and mRNA expression, as well as COX‐2 promoter activation, were inhibited by 15d‐PGJ2. Troglitazone, a selective peroxisome proliferator–activated receptor γ (PPARγ) ligand, enhanced COX‐2 expression, while GW9662, a specific PPARγ antagonist, relieved the suppressive effect of 15d‐PGJ2. IL‐1β–induced histone H3 acetylation was selectively blocked by 15d‐PGJ2. The reduction of histone H3 acetylation did not correlate with the recruitment of HDACs to the COX‐2 promoter. Also, treatment with the specific HDAC inhibitor, trichostatin A, did not relieve the suppressive effect of 15d‐PGJ2, indicating that HDACs are not involved in the inhibitory effect of 15d‐PGJ2. Furthermore, 15d‐PGJ2 blocked IL‐1β–induced recruitment of p300 to the COX‐2 promoter, which may be the mechanism for decreased histone H3 acetylation and COX‐2 expression. In accordance with this, overexpression of p300, but not of a mutant p300 lacking HAT activity, relieved the inhibitory effect of 15d‐PGJ2 on COX‐2 promoter activation.These data suggest that 15d‐PGJ2 can inhibit IL‐1β–induced COX‐2 expression by an HDAC‐independent mechanism, probably by interfering with HAT p300. [ABSTRACT FROM AUTHOR]

Membrane-associated prostaglandin (PG) E2 synthase-1 (mPGES-1) catalyzes the conversion of PGH2 to PGE2, which contributes to many biological processes. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor and plays an important role in growth, differentiation, and inflammation in different tissues. Here, we examined the effect of PPARγ legends on interleukin-1β (IL-1β)-induced mPGES-1 expression in human synovial fibroblasts. PPARγ ligands 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2) and the thiazolidinedione troglitazone (TRO), but not PPARα ligand Wy14643, dose-dependently suppressed IL-1β-induced PGE2 production, as well as mPGES-1 protein and mRNA expression. 15d-PCJ2 and TRO suppressed IL-1β-induced activation of the mPGES-1 promoter. Overexpression of wild-type PPARγ further enhanced, whereas overexpression of a dominant negative PPARγ alleviated, the suppressive effect of both PPARγ ligands. Furthermore, pretreatment with an antagonist of PPARγ, GW9662, relieves the suppressive effect of PPARγ ligands on mPGES-1 protein expression, suggesting that the inhibition of mPGES-1 expression is mediated by PPARγ. We demonstrated that PPARγ ligands suppressed Egr-1-mediated induction of the activities of the mPGES-1 promoter and of a synthetic reporter construct containing three tandem repeats of an Egr-1 binding site. The suppressive effect of PPARγ ligands was enhanced in the presence of a PPARγ expression plasmid. Electrophoretic mobility shift and supershift assays for Egr-1 binding sites in the mPGES-1 promoter showed that both 15d-PGJ2 and TRO suppressed IL-1β-induced DNA-binding activity of Egr-1. These data define mPGES-1 and Egr-1 as novel targets of PPARγ and suggest that inhibition of mPGES-1 gene transcription may be one of the mechanisms by which PPARγ regulates inflammatory responses. [ABSTRACT FROM AUTHOR]