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Background Circulating fatty acid-binding protein 4 (FABP4) influences cardiovascular disease and glucose metabolism. Acute aerobic exercise increases circulating FABP4 concentrations, but the factors underlying this effect in humans are unclear. We investigated the effect of exercise duration on circulating FABP4 concentrations in healthy men. Methods This randomized crossover study enrolled healthy young men randomly assigned to two trials, short-duration (SE) and long-duration (LE) aerobic exercises trials. Both involved acute aerobic exercise followed by 60 min of bed rest. The exercise intensity was the same (40% peak oxygen uptake); however, the duration was 40 and 70 min for the SE and LE trials, respectively. Venous blood samples were collected to measure hormones, metabolites, and FABP4 concentrations. Results Twelve healthy young men completed both trials. Changes in hormone levels did not differ significantly between the SE and LE trials ( p  > 0.05). However, the circulating FABP4 concentration increased significantly only in the LE trial immediately after exercise ( p  = 0.018). It increased significantly 30–60 min post-exercise in both the SE and LE trials ( p  < 0.018), with the extent of the increase being significantly higher in the LE trial than in the SE trial ( p  < 0.001). In each trial, the total incremental area under the curve of circulating FABP4 concentration was significantly positively correlated with body fat percentage (SE trial: r s  = 0.699, p  = 0.019; LE trial: r s  = 0.643, p  = 0.024). Conclusion Our findings suggest that exercise duration is associated with the magnitude of increased FABP4 secretion into the blood circulation. Body fat accumulation may also be involved in the magnitude of FABP4 secretion induced by acute aerobic exercise. Trial registration The study was pre-registered with the University Hospital Medical Information Network Center (UMIN), a clinical trial registration system (ID: UMIN000051068).

Zinc is essential for maintaining normal structure and physiological function of cells. Its deficiency causes growth retardation, immunodeficiency, and neuronal degeneration. Zinc homeostasis is tightly regulated by zinc transporters and metallothioneins that control zinc concentration and its distribution in individual cells and contributes to zinc signaling. The intracellular zinc signaling regulates immune reactions. Although many molecules involved in these processes have zinc-binding motifs, the molecular mechanisms and the role of zinc in immune responses have not been elucidated. We and others have demonstrated that zinc signaling plays diverse and specific roles in vivo and in vitro in studies using knockout mice lacking zinc transporter function and metallothionein function. In this review, we discuss the impact of zinc signaling focusing particularly on mast cell-, basophil-, and T cell-mediated inflammatory and allergic responses. We also describe zinc signaling dysregulation as a leading health problem in inflammatory disease and allergy.

We previously reported that rhamnan sulfate (RS) purified from Monostroma nitidum significantly suppressed lipopolysaccharide (LPS)-induced inflammation in cultured human vascular endothelial cells. Here, we analyzed the effect of orally administered RS on LPS-induced damage to mouse organs and vascular endothelium. RS (1 mg) was orally administered daily to BALB/c mice, 50 μg of LPS was intraperitoneally administered on day 8, and Evans blue was injected into the tail vein 6 h later. After 30 min, LPS-treated mice showed pulmonary Evans blue leakage and elevated plasma levels of liver damage markers, whereas this reaction was suppressed in LPS + RS-treated mice. Immunohistochemical and Western blot analysis of mouse organs 24 h after LPS treatment showed significant neutrophil infiltration into the lung, liver, and jejunum tissues of LPS-treated mice and high expression levels of inflammation-related factors in these tissues. Expression levels of these factors were significantly suppressed in LPS + RS-treated mice. Analysis of lung glycocalyx showed a significant reduction in glycocalyx in LPS-treated mice but not in LPS + RS-treated mice. Levels of syndecan-4, one of the glycocalyx components, decreased in LPS-treated mice and increased in LPS + RS-treated mice. The current results suggest that orally administered RS protects organs and vascular endothelium from LPS-induced inflammation and maintains blood circulation.

BackgroundRecently, Helicobacter pylori (HP)-uninfected gastric mucosal cancer has been reported; however, the clinicopathological and molecular features of HP-uninfected gastric cancer have not been elucidated.MethodsWe evaluated the clinicopathological, immunohistochemical, and genetic alterations in HP-uninfected early gastric adenocarcinoma using next-generation sequencing (NGS).ResultsAmong 968 primary early gastric carcinomas, 64 (6.6%) were HP-uninfected gastric adenocarcinoma and were pathologically classified as gastric adenocarcinoma of fundic-gland type (GA-FG, n = 39), differentiated gastric adenocarcinoma (DGA, n = 16), and signet-ring cell carcinoma (SRCC, n = 9). Based on the expression profile of the mucin core protein, DGAs were classified into a gastrointestinal phenotype showing either MUC5AC or MUC6 expression and MUC2 or CD10 expression simultaneously (n = 5), and a gastric phenotype (n = 11) showing either MUC5AC or MUC6 expression. All DGAs with a gastrointestinal phenotype shared similar endoscopic characteristics, such as reddish depressed lesions in the antrum. In contrast, DGAs with a gastric phenotype exhibited several distinct endoscopic features, including a raspberry-shaped appearance and whitish flat-elevated appearance; the former expressed only MUC5AC and the latter exhibited co-expression of MUC5AC and MUC6. Among 16 HP-uninfected DGAs, seven were subjected to NGS. APC was recurrently mutated in DGA (42.9%) and was enriched in DGAs with a gastrointestinal phenotype (75%).ConclusionsOverall, HP-uninfected gastric adenocarcinomas showed distinct clinicopathologic and endoscopic characteristics. Furthermore, HP-uninfected DGAs, especially those with a gastrointestinal phenotype, may be characterized by recurrent APC mutations.

Background Circulating fatty acid-binding protein 4 (FABP4) is a marker for various diseases. It would be highly useful to have simple and less invasive techniques for the assessment of FABP4 concentrations in the clinical research setting. The purpose of the present study was to assess the concordance of circulating FABP4 concentrations in venous and capillary blood both at rest and immediately after acute exercise in healthy young males. Results Thirty-eight healthy young male adults aged from 19 to 25 years (mean age, 20.8 ± 1.2 years) were recruited. Paired blood samples were taken from the cubital vein (venous) and fingertip (capillary) blood at rest (resting state) and immediately after incremental exercise (exercising state). Blood samples were analyzed to determine the circulating FABP4 concentration using an enzyme-linked immunosorbent assay. Pearson’s correlation coefficients for circulating FABP4 concentrations between venous and capillary blood samples indicated a strong positive correlation in both the resting and exercising state (resting state: r = 0.982, exercising state: r = 0.989, both p < 0.001). The mean FABP4 concentration was similar between venous and capillary blood in the resting state ( p = 0.178), whereas it was significantly higher in capillary blood than in venous blood in the exercising state ( p < 0.001). Furthermore, Bland–Altman plots showed a non-significant bias (− 0.07 ± 0.61 ng/mL, p = 0.453) in the resting state, whereas a significant bias (− 0.45 ± 0.61 ng/mL, p < 0.001) was observed in the exercising state. Conclusions These results indicate that capillary blood sampling can slightly overestimate circulating FABP4 concentrations under a physiologically dynamic state. However, the association between the venous and capillary blood in terms of FABP4 concentration was very strong, suggesting that capillary blood sampling can detect changes in FABP4 concentration in both physiologically steady and dynamic states.

Cellulase production in filamentous fungi is repressed by various carbon sources. In our preliminary survey in Aspergillus nidulans , degree of de-repression differed depending on carbon sources in a mutant of creA , encoding the transcriptional repressor for carbon catabolite repression (CCR). To further understand mechanisms of CCR of cellulase production, we compared the effects of creA deletion with deletion of protein kinase A ( pkaA ) and G ( ganB ) genes, which constitute a nutrient sensing and signaling pathway. In plate culture with carboxymethyl cellulose and d -glucose, deletion of pkaA and ganB , but not creA , led to significant de-repression of cellulase production. In submerged culture with cellobiose and d -glucose or 2-deoxyglucose, both creA or pkaA single deletion led to partial de-repression of cellulase genes with the highest level by their double deletion, while ganB deletion caused de-repression comparable to that of the creA / pkaA double deletion. With ball-milled cellulose and d -glucose, partial de-repression was detected by deletion of creA but not of pkaA or ganB . The creA / pkaA or creA / ganB double deletion led to earlier expression than the creA deletion. Furthermore, the effect of each deletion with d -xylose or L-arabinose as the repressing carbon source was significantly different from that with d -glucose, d -fructose, and d -mannose. Consequently, this study revealed that PkaA and GanB participate in CreA-independent CCR and that contribution of CreA, PkaA, and GanB in CCR differs depending on the inducers, repressing carbon sources, and culture conditions (plate or submerged). Further study of CreA-independent mechanisms is needed to fully understand CCR in filamentous fungi.

Zinc (Zn) is an essential nutrient and its deficiency causes immunodeficiency and skin disorders. Various cells including mast cells release Zn-containing granules when activated; however, the biological role of the released Zn is currently unclear. Here we report our findings that Zn transporter ZnT2 is required for the release of Zn from mast cells. In addition, we found that Zn and mast cells induce IL-6 production from inflammatory cells such as skin fibroblasts and promote wound healing, a process that involves inflammation. Zn induces the production of a variety of pro-inflammatory cytokines including IL-6 through signaling pathways mediated by the Zn receptor GPR39. Consistent with these findings, wound healing was impaired in mice lacking IL-6 or GPR39. Thus, our results show that Zn and mast cells play a critical role in wound healing through activation of the GPR39/IL-6 signaling axis.

Background Fatty acid-binding protein 4 (FABP4) has been associated with cardiovascular disease and diabetes. Acute aerobic exercise increases circulating FABP4 concentrations, but the underlying mechanisms remain unclear. The purpose of this study was to investigate the effects of inhibition of lipolysis by carbohydrate ingestion on circulating FABP4 concentrations during and after acute aerobic exercise in healthy men. Methods Men aged between 20 and 40, with no exercise habits and no metabolic diseases, were recruited. In a randomized crossover design, the participants underwent a carbohydrate-ingestion exercise (CE) and a fasted exercise (FE) trial. The CE trial consisted of 40-min acute aerobic exercise with ingestion of carbohydrates and 60-min bed rest. The FE trial followed the same protocol as the CE trial but without carbohydrate ingestion. Venous blood samples were collected to measure hormones (adrenaline, noradrenaline, and insulin) metabolites (glycerol, free fatty acids, and glucose), and FABP4 concentrations. Ventilation and gas exchange were also collected to measure substrate oxidation. Results Thirteen healthy men participated in and completed both the CE and FE trials. The insulin concentration was more than 4 times higher in the CE trial than in the FE trial ( p  < 0.004, effect size [ES] > 2.00). Free fatty acid concentrations were more than 4 times lower in the CE trial than in the FE trial ( p  < 0.02, ES > 2.04). However, there was no significant difference in the changes in circulating FABP4 concentrations between the CE and FE trials ( p  = 0.108), which did not change during aerobic exercise and significantly increased post-aerobic exercise in both trials ( p  < 0.002, ES > 1.212). Changes in FABP4 concentrations following aerobic exercise were not significantly correlated with changes in glycerol or free fatty acid concentrations during aerobic exercise. Conclusions The results suggest that suppression of lipolysis and elevation of insulin are not strongly involved in increases in FABP4 secretion following acute aerobic exercise.

Carbon catabolite repression (CCR) enables preferential utilization of easily metabolizable carbon sources, implying the presence of mechanisms to ensure discriminatory gene repression depending on the ambient carbon sources. However, the mechanisms for such hierarchical repression are not precisely understood. In this report, we examined how deletion of pkaA and ganB, which encode cAMP signaling factors, and creA, which encodes a well-characterized repressor of CCR, affects CCR of hemicellulase genes in the filamentous fungus Aspergillus nidulans. β-Xylanase production increased not only in ΔcreA but also in ΔpkaA and ΔganB, with the highest level observed in their double deletants, irrespective of the presence or absence of d-glucose. Expression of the β-xylanase genes in the presence of d-glucose was de-repressed in all the deletion mutants, with significantly higher tolerance against d-glucose repression in ΔpkaA and ΔganB than in ΔcreA. In the presence of galactomannan and d-glucose, partial de-repression of β-mannanase production was detected in ΔcreA, but not in ΔpkaA and ΔganB. The double deletion of creA/pkaA and creA/ganB led to earlier production. Release from d-glucose repression of the β-mannanase genes was partial in the single deletants, while nearly full de-repression was observed in ΔcreAΔpkaA and ΔcreAΔganB. The contribution of PkaA and GanB to CCR by d-xylose of the β-mannanase genes was very minor compared to that of CreA. Consequently, the present study revealed that cAMP signaling plays a major role in CCR of hemicellulase gene expression in a manner that is clearly independent from CreA.