Summary
Background
Nasal polyposis is a multi‐factorial disease associated with chronic inflammatory condition of the paranasal sinuses. Myofibroblast differentiation and extracellular matrix (ECM) ...accumulation are involved in the pathogenesis of nasal polyposis.
Objective
The aim of this study was to study the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on transforming growth factor (TGF)‐β1‐induced myofibroblast differentiation and ECM accumulation in nasal polyp‐derived fibroblasts (NPDFs).
Methods
Nasal polyp‐derived fibroblasts were isolated from nasal polyps of patients who have chronic rhinosinusitis with nasal polyp. TSA was treated in TGF‐β1‐induced NPDFs. Expression levels of HDAC2, α‐smooth muscle actin (SMA), TGF‐β1, collagen type I, acetylated Histone H3, acetylated Histone H4, phosphorylated Smad2/3 and Smad7 were determined by RT‐PCR, western blot and/or immunofluorescent staining. The total collagen amount production was analysed by Sircol soluble collagen assay and contractile activity was measured by collagen gel contraction assay. HDAC2 inhibition by TSA or HDAC2 silencing was established by RT‐PCR and western blot. The epigenetic effect on α‐SMA gene inactivation was examined by chromatin immunoprecipitation assay. Proliferation was determined by Ki67‐positive cell staining and cytotoxicity was assessed by 3‐(4,5‐ dimethylthiazol‐2yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay.
Results
The expression levels of HDAC2, α‐SMA and TGF‐β1 were increased in nasal polyp tissues compared to normal inferior turbinate tissues. TSA and HDAC2 silencing inhibited expression levels α‐SMA, collagen and HDAC2. TSA induced hyperacetylation of histone and suppressed opening of α‐SMA gene promoter in TGF‐β1‐induced NPDFs. TSA inhibited TGF‐β1‐induced Smad 2/3 and rescued TGF‐β1‐suppressed Smad7 signalling pathway. Finally, TSA blocked proliferation in TGF‐β1‐induced NPDFs and has no cytotoxic effect in NPDFs.
Conclusions and Clinical Relevance
These results suggest that HDAC inhibition is associated with myofibroblast differentiation and extracelluar matrix accumulation in nasal polyposis. TSA may be useful as an inhibitor of nasal polyp growth, and thus has potential to be used as a novel treatment option for nasal polyposis.
Summary
Smoking is a major environmental factor associated with periodontal diseases. However, we still have a very limited understanding of the relationship between smoking and subgingival ...microflora in the global population. Here, we investigated the composition of subgingival bacterial communities from the pooled plaque samples of smokers and non‐smokers, 134 samples in each group, in Korean patients with moderate chronic periodontitis using 16S rRNA gene‐based pyrosequencing. A total of 17,927 reads were analyzed and classified into 12 phyla, 126 genera, and 394 species. Differences in bacterial communities between smokers and non‐smokers were examined at all phylogenetic levels. The genera Fusobacterium, Fretibacterium, Streptococcus, Veillonella, Corynebacterium, TM7, and Filifactor were abundant in smokers. On the other hand, Prevotella, Campylobacter, Aggregatibacter, Veillonellaceae GQ422718, Haemophilus, and Prevotellaceae were less abundant in smokers. Among species‐level taxa occupying > 1% of whole subgingival microbiome of smokers, higher abundance (≥ 2.0‐fold compared to non‐smokers) of seven species or operational taxonomic units (OTUs) was found: Fusobacterium nucleatum, Neisseria sicca, Neisseria oralis, Corynebacterium matruchotii, Veillonella dispar, Filifactor alocis, and Fretibacterium AY349371. On the other hand, lower abundance of 11 species or OTUs was found in smokers: Neisseria elongata, six Prevotella species or OTUs, Fusobacterium canifelinum, Aggregatibacter AM420165, Selenomonas OTU, and Veillonellaceae GU470897. Species richness and evenness were similar between the groups whereas diversity was greater in smokers than non‐smokers. Collectively, the results of the present study indicate that differences exist in the subgingival bacterial community between smoker and non‐smoker patients with chronic moderate periodontitis in Korea, suggesting that cigarette smoking considerably affects subgingival bacterial ecology.
Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ ...dysfunction, age, genetics) and extrinsic (e.g., drug–drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision‐making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.
Clinical Pharmacology & Therapeutics (2011) 89 2, 259–267. doi:10.1038/clpt.2010.298
Rapidly decaying oscillations of the thermal emission detected in the decay phase of solar and stellar flares are usually interpreted as standing or sloshing (reflecting) slow magnetoacoustic ...oscillations. We determine the scalings of the oscillation periods, damping times, and amplitudes with the temperature, considering both standing and sloshing oscillations detected with different instruments. In addition, the time evolution of different spatial harmonics of a sloshing oscillation is considered. Parameters of slow oscillations observed in the EUV, X-ray, and microwave bands, and published in the literature, are used. The damping time of slow oscillations is found to scale almost linearly with the oscillation period, as the period to 0.87 0.1, giving the average Q-factor determined as the ratio of the damping time to the period, of about 1. The Q-factor is found to scale with the relative amplitude to the power of with 95% confidence. The amplitudes of different spatial harmonics forming a sloshing pulse show similar time evolution, suggesting that the period-dependent dissipation is counteracted by another mechanism. The results obtained indicate that the damping of slow oscillations depends on the oscillation amplitude, and that the competition of nonlinear and dissipative effects could allow for the existence of wave pulses of a sustained shape.
Thirteen outbreaks of foot‐and‐mouth disease (FMD) were reported in pigs and cattle in Korea between 8 April and 4 June 2010. The FMD virus (FMDV) isolates were of serotype O, indicating that they ...were related to the virus strains of the Southeast Asia topotype that are circulating in East Asian countries. Animals carrying the viruses were identified by reverse transcriptase‐polymerase chain reaction (RT‐PCR) during a 29‐day period between 8 April and 6 May, 2010. Prior to this outbreak, these FMDVs had not been detected in Korea and may therefore have been introduced from neighbouring countries into Ganghwa Island and subsequently spread inland to other areas, including Gimpo, Chungju and Cheongyang. Tests conducted to lift restrictions on animal movements lead to detection of two additional FMD‐positive farms. Through appropriate responses, including swift diagnoses and culling policies, Korea was able to quickly regain its recognition as being free of FMD, without vaccination, by the World Organization for Animal Health (OIE) on 27 September 2010.
Summary Objective The present study was performed to elucidate the possible role of SIRT1 signaling in joint inflammation in human articular chondrocytes. Design Real-time quantitative reverse ...transcription polymerase chain reaction (qRT-PCR) and Western blotting were performed to detect gene products and proteins involved in tumor necrosis factor α (TNF-α)-induced inflammation and cartilage degradation in human primary chondrocytes. Matrix metalloproteinase (MMP)-2 and MMP-9 activity was evaluated by gelatin zymography. Overexpression and knockdown of SIRT1 were also performed to investigate whether SIRT1 is associated with the anti-inflammatory activity of resveratrol in chondrocytes. Results Resveratrol dose-dependently inhibited TNF-α-induced cyclooxygenase-2 (COX-2), MMP-1, MMP-3, MMP-13 and PGE2 production in human chondrocytes. Moreover, MMP-2 and MMP-9 activity was increased by treatment with TNF-α; however, SIRT1 activation decreased the proinflammatory effects induced by TNF-α. In addition, treatment of SIRT1 activator and overexpression of SIRT1 inhibited the expression and activation of the main proinflammatory regulator NF-κB, which was increased by TNF-α. When SIRT1 was overexpressed in chondrocytes, the anti-inflammatory action of SIRT1 was similar to that exerted by resveratrol. Conclusions SIRT1 activation deacetylates and inactivates NF-κB, and thereby, exerts an anti-inflammatory effect on chondrocytes, suggesting that SIRT1 activators could be explored as potential treatments for arthritis.
Abstract
The magnetocaloric effect (MCE) is described by the change in temperature of a material by magnetic field variation and is a crucial subject in magnetism; it is motivated by the desire to ...enhance energy-efficient magnetic refrigeration for clean technology. Despite the recent discovery of the giant cryogenic MCE in double perovskites, the role of magnetic anisotropy has not yet been clearly discussed, because of the averaging effect of polycrystalline samples. Here, we investigated the anisotropic MCE in the single-crystal double perovskite Gd
2
CoMnO
6
. In addition to the ferromagnetic order of the Co
2+
and Mn
4+
moments, the large Gd
3+
moments align below
T
Gd
= 21 K, exhibiting an isotropic nature. Because of the intricate temperature development of magnetically hysteretic behaviour and metamagnetism, the change in magnetic entropy along the
c
-axis appears to be relatively small. On the contrary, the smaller but almost reversible magnetization perpendicular to the
c-
axis leads to a large MCE with a maximum entropy change of 25.4 J/kg·K. The anisotropic MCE generates a giant rotational MCE, estimated as 16.6 J/kg·K. Our results demonstrate the importance of magnetic anisotropy for understanding the MCE and reveal essential clues for exploring suitable magnetic refrigerant compounds aiming at magnetic functional applications.
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