IL-1Ra regulates IL-1 activity and appears to reduce the levels of other inflammatory cytokines, including TNF-α and IL-6, while it also reduces expression of the EP4 receptor related to prostanoid sensitivity and osteoclast formation. These results suggest that IL-1Ra is an important molecule for inhibition of inflammatory periodontal bone resorption.

This study analyzes the effect of interleukin-15 (IL-15) on osteoclast formation using a coculture of mouse osteoblasts and bone marrow cells (BMCs) stimulated with prostaglandin E2 (PGE2), which both have important role in rheumatoid arthritis (RA) and periodontal disease (PD). BMCs isolate lacking T (BM(T-)) or NK (BM(NK-)) cells, BMCs with no cells removed (BM(T+NK+)), purified NK cells, and purified T cells were each cocultured with osteoblasts in the presence or absence of PGE2 and/or IL-15. The number of both osteoclasts and osteoblasts was decreased by IL-15 in a dose-dependent manner in BM(T+NK+), BM(T-). However, the reductions were improved in BM(NK-). The expression of caspase3 in osteoblasts cocultured with NK cells was increased in a dose-dependent manner by IL-15. IL-15 stimulates apoptosis of osteoblasts via activation of NK cells. Since osteoblasts have an important role in bone formation, IL-15 may be an inflammatory bone destructive factor in RA and PD.

cThe interleukin-1 receptor antagonist (IL-1Ra) binds to IL-1 receptors and inhibits IL-1 activity. However, it is not clear whether IL-1Ra plays a protective role in periodontal disease. This study was undertaken to compare experimental periodontitis induced by Aggregatibacter actinomycetemcomitans in IL-1Ra knockout (KO) mice and wild-type (WT) mice. Computed tomography (CT) analysis and hematoxylin-and-eosin (H&E) and tartrate-resistant acid phosphatase (TRAP) staining were performed. In addition, osteoblasts were isolated; the mRNA expression of relevant genes was assessed by real-time quantitative PCR (qPCR); and calcification was detected by Alizarin Red staining. Infected IL-1Ra KO mice exhibited elevated (P, <0.05) levels of antibody against A. actinomycetemcomitans, bone loss in furcation areas, and alveolar fenestrations. Moreover, protein for tumor necrosis factor alpha (TNF-␣) and IL-6, mRNA for macrophage colony-stimulating factor (M-CSF), and receptor activator of NF-B ligand (RANKL) in IL-1Ra KO mouse osteoblasts stimulated with A. actinomycetemcomitans were increased (P, <0.05) compared to in WT mice. Alkaline phosphatase (ALP), bone sialoprotein (BSP), osteocalcin (OCN)/bone gla protein (BGP), and runt-related gene 2 (Runx2) mRNA levels were decreased (P, <0.05). IL-1␣ mRNA expression was increased, and calcification was not observed, in IL-1 Ra KO mouse osteoblasts. In brief, IL-1Ra deficiency promoted the expression of inflammatory cytokines beyond IL-1 and altered the expression of genes involved in bone resorption in A. actinomycetemcomitans-infected osteoblasts. Alterations consistent with rapid bone loss in infected IL-Ra KO mice were also observed for genes expressed in bone formation and calcification. In short, these data suggest that IL-1Ra may serve as a potential therapeutic drug for periodontal disease.

We investigate high-order harmonic generation from D 2 /H 2 molecules with intense multi-cycle pulses centred both at 1300 nm (60 fs) and at 800 nm (50 fs) together with that from N 2 /Ar as a reference. The experimental observations with 1300 nm pulses are different from those with 800 nm pulses both in spectral shapes and in intensity ratios I D 2 /I H 2 . The effect of nuclear motion in D 2 and H 2 is more distinctive for 1300 nm pulses than for 800 nm pulses. With multi-cycle pulses of 50-60 fs, the intensity ratios I D 2 /I H 2 are found to be higher for both 800 nm and 1300 nm pulses than those with few-cycle pulses of 8 fs, which is attributed partly to the contribution of the coupling between the 1sσ g and 2pσ u states in D + 2 and H + 2 molecular ions during the higher order returns of the electron wave packets.

(1) Objective: hypercoagulability in patients with malignant neoplasm were evaluated to examine the relationship with thrombosis. (2) Methods: clot waveform analysis (CWA)—activated partial thromboplastin time (APTT) and CWA—small amount of tissue factor induced FIX activation (sTF/FIXa) assays were performed in 92 patients with malignant neoplasm and the relationship between hypercoagulability and thrombosis was retrospectively examined. (3) Results: The study population included 92 patients with malignant neoplasms. Twenty-six (28.3%) had thrombotic diseases and 9 (9.8%) patients died within 28 days after the CWA. The peak time of the CWA-APTT could not show hypercoagulability in patients with malignant neoplasms. There were almost no significant differences in the peak times of the sTF/FIXa among patients with malignant neoplasms and healthy volunteers. In contrast, the peak heights of the CWA-sTF/FIXa in patients with various malignant neoplasms were significantly higher than those in healthy volunteers. Furthermore, among patients with malignant neoplasms, the peak heights of the sTF/FIXa in patients with thrombosis were significantly higher than those in patients without thrombosis. (4) Conclusions: although the routine APTT cannot evaluate the hypercoagulability, the peak heights of CWA-sTF/FIXa were significantly high in patients with malignant neoplasms, especially in those with thrombosis, suggesting that an elevated peak height of the CWA-sTF/FIXa may be a risk factor for thrombosis.

No abstract

High-mobility group box 1 (HMGB1) is a nuclear factor and a secreted protein. During inflammation, HMGB1 is secreted into the extracellular space where it can interact with the receptor for advanced glycation end products and trigger proinflammatory signals. Extracellular HMGB1 plays a critical role in several inflammatory diseases such as sepsis and rheumatoid arthritis. Valproic acid (VPA) is one of the most frequently prescribed antiepileptic drugs. The present study was undertaken to investigate the effect of VPA on secretion of HMGB1 in systemic inflammatory responses induced by lipopolysaccharide. Pretreatment with VPA increased the susceptibility of mice to lipopolysaccharide in endotoxemia. Valproic acid induced HMGB1 release and nuclear factor κB activation in RAW-blue cells. Valproic acid promoted the phosphorylation of ERK1/2 but not that of p38 or JNK. The MEK1/2 inhibitor PD98059 also suppressed HMGB1 release and activation of nuclear factor κB induced by VPA. Valproic acid induced expression of γ-aminobutyric acid receptors in macrophages, and picrotoxin, a γ-aminobutyric acid A receptor antagonist, inhibited the VPA-activated phosphorylation of ERK and VPA-induced HMGB1 release. These results suggest that VPA may exacerbate innate immune responses to endotoxin through enhanced release of HMGB1.

Background Gut pathological microbial imbalance or dysbiosis is closely associated with colorectal cancer. Although there are observable differences in molecular and clinical characteristics between patients with right- and left-sided colon cancer, differences in their gut microbiomes have not been thoroughly investigated. Furthermore, subsequent changes in microbiota status after partial colectomy remain unknown. We examined the human gut microbiota composition to determine its relationship with colon cancer and partial colon resection according to location. Methods Stool samples from forty-one subjects (10 in the control group, 10 in the right-sided colon cancer [RCC] group, 6 in the sigmoid colon cancer [SCC] group, 9 in the right colon resection [RCR] group and 6 in the sigmoid colon resection [SCR] group) were collected, and DNA was extracted. After terminal restriction fragment length polymorphism (T-RFLP) analysis, the samples were subjected to 16S rRNA gene amplicon sequencing, and the metabolic function of the microbiota was predicted using PICRUSt2. Results T-RFLP analysis showed a reduced ratio of clostridial cluster XIVa in the SCC patients and clostridial cluster IX in the RCC patients, although these changes were not evident in the RCR or SCR patients. 16S rRNA gene amplicon sequencing demonstrated that the diversity of the gut microbiota in the RCC group was higher than that in the control group, and the diversity in the SCR group was significantly higher than that in the RCR group. Principal coordinate analysis (PCoA) revealed significant differences according to the group. Analyses of the microbiota revealed that Firmicutes was significantly dominant in the RCC group and that the SCC group had a higher abundance of Verrucomicrobia. At the genus level, linear discriminant analysis effect size (LEfSe) revealed several bacteria, such as Ruminococcaceae, Streptococcaceae, Clostridiaceae, Gemellaceae, and Desulfovibrio, in the RCC group and several oral microbiomes in the SCC group. Metabolic function prediction revealed that cholesterol transport- and metabolism-related enzymes were specifically upregulated in the RCC group and that cobalamin metabolism-related enzymes were downregulated in the SCC group. Conclusion Gut microbial properties differ between RCC and SCC patients and between right hemicolectomy and sigmoidectomy patients and may contribute to clinical manifestations.