An Orally Administered Redox Nanoparticle That Accumulates in the Colonic Mucosa and Reduces Colitis in Mice

Background & AimsDrugs used to treat patients with ulcerative colitis are not always effective because of nonspecific distribution, metabolism in the gastrointestinal tract, and side effects. We designed a nitroxide radical-containing nanoparticle (RNPO) that accumulates specifically in the colon to suppress inflammation and reduce the undesirable side effects of nitroxide radicals.MethodsRNPO was synthesized by assembly of an amphiphilic block copolymer that contains stable nitroxide radicals in an ether-linked hydrophobic side chain. Biodistribution of RNPO in mice was determined from radioisotope and electron spin resonance measurements. The effects of RNPO were determined in mice with dextran sodium sulfate (DSS)-induced colitis and compared with those of low-molecular-weight drugs (4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl [TEMPOL] or mesalamine).ResultsRNPO, with a diameter of 40 nm and a shell of poly(ethylene glycol), had a significantly greater level of accumulation in the colonic mucosa than low-molecular-weight TEMPOL or polystyrene latex particles. RNPO was not absorbed into the bloodstream through the intestinal wall, despite its long-term retention in the colon, which prevented its distribution to other parts of the body. Mice with DSS-induced colitis had significantly lower disease activity index and less inflammation following 7 days of oral administration of RNPO compared with mice with DSS-induced colitis or mice given low-molecular-weight TEMPOL or mesalamine.ConclusionsWe designed an orally administered RNPO that accumulates specifically in the colons of mice with colitis and is more effective in reducing inflammation than low-molecular-weight TEMPOL or mesalamine. RNPO might be developed for treatment of patients with ulcerative colitis

Quark Spectrum above but near Critical Temperature of Chiral Transition

We explore the quark properties at finite temperature near but above the critical temperature of the chiral phase transition. We investigate the effects of the precursory soft mode of the phase transition on the quark dispersion relation and the spectral function. It is found that there appear novel excitation spectra of quasi-quarks and quasi-antiquarks with a three-peak structure, which are not attributed to the hard-thermal-loop approximation. We show that the new spectra originate from the mixing between a quark (anti-quark) and an anti-quark hole (quark hole) caused by a ``resonant scattering'' of the quasi-fermions with the thermally-excited soft mode which has a small but finite excitation energy.Comment: 6 pages, 12 eps figures, typos corrected and references updated, version to appear in Phys. Lett.

Suppression of NSAID-induced small intestinal inflammation by orally administered redox nanoparticles

Patients regularly taking non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (IND) have a risk of small intestinal injuries. In this study, we have developed an oral nanotherapeutics by using a redox nanoparticle (RNPO), which is prepared by self-assembly of an amphiphilic block copolymer that possesses nitroxide radicals as side chains of hydrophobic segment via ether linkage, to reduce inflammation in mice with IND-induced small intestinal injury. The localization and accumulation of RNPO in the small intestine were determined using fluorescent-labeled RNPO and electron spin resonance. After oral administration, the accumulation of RNPO in both the jejunum and ileum tissues was about 40 times higher than those of low-molecular-weight nitroxide radical compounds, and RNPO was not absorbed into the bloodstream via the mesentery, thereby avoiding the adverse effects of nitroxide radicals in the entire body. RNPO remarkably suppressed inflammatory mediators such as myeloperoxidase, superoxide anion, and malondialdehyde in the small intestines of IND-treated mice. Compared to low-molecular-weight nitroxide radical compounds, RNPO also significantly increased the survival rate of mice treated daily with IND. On the basis of these results, RNPO is promising as a nanotherapeutics for treatment of inflammation in the small intestine of patients receiving NSAIDs

A Dipeptidyl Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin, Improves Endothelial Function and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E–Deficient Mice

ObjectivesThe aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS).BackgroundThe new class of anti–type 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1.MethodsEndothelial function was examined by acetylcholine-induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E–deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease.ResultsDFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10−4 mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001).ConclusionsA DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium

Vulnerability of Roof and Building Walls Under a Translating Tornado Like Vortex

Exposure of a building to a tornado often proves fatal, resulting in massive destruction of property and structures. The effect of disasters can be minimized by understanding the nature of fluid-structure interactions when a tornado hits a building on its path. Earlier researchers have investigated extensively on building models exposed to stationary type vortex generated in a laboratory type tornado simulator; however studies using translating type vortex are few. In the present investigation, the external and internal pressures experienced by a building model are discussed based on experiments conducted using a translating tornado-like flow simulator at Tokyo Polytechnic University, Japan. The swirl ratio which characterizes the strength of vortices generated is kept constant. The investigation attempts to explore the opening locations which can result in higher internal pressures and net roof forces in building and the vulnerability of roof structures of buildings when exposed to tornado-like flow. The effect of translating speed on internal pressure fluctuations when compared to those of external pressures are investigated using aerodynamic admittance functions. Results indicate that there is an increased amount of internal pressure fluctuations at higher translating speeds

RETRACTED: The Chromatin-Remodeling Complex WINAC Targets a Nuclear Receptor to Promoters and Is Impaired in Williams Syndrome

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Authors.Our paper reported that a chromatin-remodeling complex, WINAC, recruited the unliganded vitamin D receptor to promoters in cooperation with the transcription factor implicated in Williams syndrome, WSTF. The findings provided insights into the coordination between chromatin remodelers and sequence-specific transcription factors and pointed to a role of chromatin remodeling defects in Williams syndrome. We recently identified errors affecting several figure panels where original data were processed inappropriately such that the figure panels do not accurately report the original data. We believe that the most responsible course of action is to retract the paper. We sincerely apologize to the scientific community for any inconvenience that this might cause. The first author, H.K., declined to sign the retraction notice

Josephson current in s-wave superconductor / Sr_2RuO_4 junctions

The Josephson current between an s-wave and a spin-triplet superconductor Sr$_2$RuO$_4$ (SRO) is studied theoretically. In spin-singlet / spin-triplet superconductor junctions, there is no Josephson current proportional to $\sin \phi$ in the absence of the spin-flip scattering near junction interfaces, where $\phi$ is a phase-difference across junctions. Thus a dominant term of the Josephson current is proportional to $\sin 2\phi$ . The spin-orbit scattering at the interfaces gives rise to the Josephson current proportional to $\cos\phi$, which is a direct consequence of the chiral paring symmetry in SRO