BMP3b Is a Novel Antifibrotic Molecule Regulated by Meflin in Lung Fibroblasts.

Fibroblasts play a central role in the lung fibrotic process. Our recent study identified a novel subpopulation of lung fibroblasts expressing meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue), antifibrotic properties of which were confirmed by murine lung fibrosis model. Meflin-expressing fibroblasts were resistant to fibrogenesis induced by TGF-ß (transforming growth factor-ß), but its underlying mechanisms remain unknown. In this study, evaluation of a silica-nanoparticle-induced lung fibrosis model confirmed the antifibrotic effect of meflin via the regulation of TGF-ß signaling. We conducted comparative gene expression profiling in lung fibroblasts, which identified growth differentiation factor 10 (Gdf10) encoding bone morphogenic protein 3b (BMP3b) as the most downregulated gene in meflin-deficient cells under the profibrotic condition with TGF-ß. We hypothesized that BMP3b can be an effector molecule playing an antifibrotic role downstream of meflin. As suggested by single-cell transcriptomic data, restricted expressions of Gdf10 (Bmp3b) in stromal cells including fibroblasts were confirmed. We examined possible antifibrotic properties of BMP3b in lung fibroblasts and demonstrated that Bmp3b-null fibroblasts were more susceptible to TGF-ß-induced fibrogenic changes. Furthermore, Bmp3b-null mice exhibited exaggerated lung fibrosis induced by silica-nanoparticles in vivo. We also demonstrated that treatment with recombinant BMP3B was effective against TGF-ß-induced fibrogenesis in fibroblasts, especially in the suppression of excessive extracellular matrix production. These lines of evidence suggested that BMP3b is a novel humoral effector molecule regulated by meflin which exerts antifibrotic properties in lung fibroblasts. Supplementation of BMP3B could be a novel therapeutic strategy for fibrotic lung diseases.

Pre-therapeutic nutritional assessment for predicting severe adverse events in patients with head and neck cancer treated by radiotherapy.

BACKGROUND & AIMS: Malnutrition is common in patients with head and neck cancer (HNSCC). It may be related to severe adverse toxicity as a result of radiotherapy. The aim was to investigate nutritional screening factors for severe adverse events. METHODS: A retrospective chart review of 101 patients who underwent radiotherapy from 2009 to 2013 was performed. The relationships among severe adverse events and pretreatment nutritional parameters, including static variables (serum albumin, total protein, total lymphocyte counts, body mass index), dynamic variables (retinol-binding protein, transferrin, pre-albumin), and nutritional screening tools (Onodera's Prognostic Nutrition Index [O-PNI]; Nutrition Risk Index; Controlling Nutritional Status [CONUT] score; Nutritional Risk Screening 2002) were evaluated in addition to patient and treatment factors. RESULTS: According to the static parameters, approximately 30% of patients were malnourished before treatment. Twenty-four patients exhibited severe adverse events. On univariate analysis, combined chemotherapy, advanced staging, O-PNI <40, and CONUT score ≥5 were significant predictors of severe adverse events. Multivariate analysis revealed that O-PNI <40 and combined chemotherapy independently predict severe adverse events. CONCLUSIONS: O-PNI is considered a useful nutritional factor for predicting severe adverse events in HNSCC patients undergoing chemoradiotherapy and facilitates the planning of aggressive nutritional interventions prior to treatment.

Glucosamine Downregulates the IL-1ß-Induced Expression of Proinflammatory Cytokine Genes in Human Synovial MH7A Cells by O-GlcNAc Modification-Dependent and -Independent Mechanisms.

Osteoarthritis (OA) is one of the major joint diseases, and the synovial inflammation is involved in the pathogenesis and progression of OA. Glucosamine (GlcN) is widely used as a dietary supplement for OA, and is expected to exert the antiinflammatory action in OA. However, the detailed mechanism for the antiinflammatory action of GlcN remains poorly understood. In this study, to elucidate the molecular mechanism involved in the GlcN-medicated regulation of synovial cell activation, we comprehensively analyzed the effect of GlcN on the gene expression using a human synovial cell line MH7A by DNA microarray. The results indicated that GlcN significantly downregulates the expression of 187 genes (≤1/1.5-fold) and upregulates the expression of 194 genes (≥1.5-fold) in IL-1ß-stimulated MH7A cells. Interestingly, pathway analysis indicated that among the 10 pathways into which the GlcN-regulated genes are categorized, the 4 pathways are immune-related. Furthermore, GlcN suppressed the expression of proinflammatory cytokine genes (such as IL-6, IL-8, IL-24 and TNF-α genes). In addition, GlcN-mediated O-GlcNAc modification was involved in the downregulation of TNF-α and IL-8 genes but not IL-6 and IL-24 genes, based on the effects of alloxan, an O-GlcNAc transferase inhibitor. Thus, GlcN likely exerts an antiinflammatroy action in OA by suppressing the expression of proinflammatory cytokine genes in synovial MH7A cells by O-GlcNAc modification-dependent and -independent mechanisms.

Risk stratification by the lower limit of normal of FEV1/FVC for postoperative outcomes in patients with COPD undergoing thoracic surgery.

BACKGROUND: Mounting evidence suggests that airway obstruction defined by the lower limit of normal (LLN) of forced expiration volume in 1s (FEV1)/forced vital capacity (FVC) might be an important predictor of mortality in patients with an FEV1/FVC ratio below 0.70. Although better risk stratification for postoperative outcomes in patients with chronic obstructive pulmonary disease (COPD) undergoing thoracic surgery is warranted, whether an FEV1/FVC ratio below 0.70 but above the LLN (i.e., in-between) could identify patients at risk for adverse postoperative outcomes has not been fully evaluated. METHODS: To determine the clinical impact of this "in-between" group of patients with COPD, we evaluated whether classification of the in-between group and the COPD group with FEV1/FVC ratios below 0.70 and below the LLN could provide more accurate risk stratification for postoperative outcomes in COPD patients undergoing thoracic surgery. RESULTS: The criterion of LLN classified 302 patients with an FEV1/FVC ratio below 0.70 into either the in-between group (124 cases) or the COPD group (178 cases). The COPD group showed a 3-fold increase in prolonged oxygen therapy (POT) and a 50% increase in prolonged postoperative stay (PPS), as compared with the in-between group, with an adjusted odds ratio of 3.068 (95% confidence interval: 1.806-5.213) for POT. CONCLUSIONS: Based on the finding that the in-between group could independently identify patients at risk for adverse postoperative outcomes, LLN assessment of the FEV1/FVC ratio might provide more accurate risk stratification in COPD patients undergoing thoracic surgery.

Effect of citrate ions on the softening of root crops prepared with freeze-thaw impregnation of macerating enzymes.

UNLABELLED: Freeze-thaw impregnation is a technique used for the rapid impregnation of substances into foodstuffs. Freeze-thaw impregnation with macerating enzymes has been applied to soften foodstuffs, while retaining their original shapes and flavors. In this study, we found that co-impregnation with citrate ions and macerating enzymes significantly facilitated the softening of root crops. When burdock roots were processed by the impregnating solution at pH 4.0-5.0, co-impregnated burdock roots exhibited 1/6-1/3 firmness values compared with burdock roots impregnated with only enzymes. The impregnation with citrate ions alone at pH 4.0 to 5.0 did not soften burdock roots. The firmness of burdock roots was positively correlated with the amount of water-insoluble calcium in the samples. The results suggested that the degradation of pectins by pectinolytic activities could promote contact with citrate to bridging-calcium ions interacting with the pectin chains. Therefore, the softening by the synergistic effect of citrate ions and macerating enzymes was related to the amount of pectins contained in root crops. That is, the synergistic effect was significant with burdock roots and carrots (from which 50% of polysaccharides are pectins) unlike with lotus rhizomes and bamboo shoots (from which 30% and 10% of polysaccharides are pectins, respectively). PRACTICAL APPLICATION: Freeze-thaw impregnation with macerating enzymes and citrate ions can be applied for the production of care foods which can be eaten without chewing. The softened products induce the pleasure of eating for consumers because their original shapes and flavors are retained.

Biological activities of glucosamine and its related substances.

Glucosamine (GlcN) has been widely used to treat osteoarthritis (OA) in humans. We revealed that among GlcN-derivatives (GlcN and N-acetyl-d-glucosamine) and uronic acids (d-glucuronic acid and d-galacturonic acid), only GlcN induces the production of hyaluronic acid (HA) by synovial cells and chondrocytes, and the production level is much higher (>10-fold) in synovial cells compared with chondrocytes. Moreover, GlcN increases the expression of HA-synthesizing enzymes (HAS) in synovial cells and chondrocytes. These observations indicate that GlcN likely exhibits the chondroprotective action on OA by modulating the expression of HAS and inducing the production of HA (a major component of glycosaminoglycans contained in the synovial fluid) especially by synovial cells. The pathological change of subchondral bone is implicated in the initiation and progression of cartilage damage in OA. Thus, we further determined the effect of GlcN on the bone metabolism (osteoblastic cell differentiation). The results indicated that GlcN increases the mineralization of mature osteoblasts and the expression of middle and late stage markers (osteopontin and osteocalcin, respectively) during osteoblastic differentiation, and reduces the expression of receptor activator of NF-κB ligand (RANKL), a differentiation and activation factor for osteoclasts. These observations likely suggest that GlcN has a potential to induce the osteoblastic cell differentiation and suppress the osteoclastic cell differentiation, thereby increasing bone matrix deposition and decreasing bone resorption to modulate bone metabolism in OA.

Evaluation of aroma compounds contributing to muskmelon flavor in Porapak Q extracts by aroma extract dilution analysis.

The flavor of the Miyabi variety of Japanese muskmelon was extracted according to the Porapak Q column method (PQM) and evaluated by using aroma extract dilution analysis (AEDA) method. The overall odor of the PQM extracts was perceived as having a natural muskmelon-like odor, suggesting that the PQM was able to extract volatile compounds in muskmelon fruit without degradation of original flavor. Forty-six odorant compounds [Kovats index (KI), 961 < or = KI < or = 2605] were found by GC-sniffing in PQM extracts, confirming the effectiveness of PQM in trapping a wide range of volatile compounds in muskmelon flavor. The 46 odorants could be divided into three groups on the basis of their odor attributes: fruity note (KI < 1300); green, grassy, or cucumber-like note (1300 < KI < 2020); and sweet note (KI > 2020). When the original extracts were diluted in AEDA analysis, seven odorants could still be detected by GC-sniffing at a flavor diluation (FD) factor of 128 or above: one had a fruity note (compound 3); four had a cucumber-like, green, or grassy note (compounds 12, 17, 21, and 23); and two had a sweet note (caramel-like or yakitori-like) (compounds 32 and 34).