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During periods of fasting, the body undergoes a metabolic shift from carbohydrate utilization to the use of fats and ketones as an energy source, as well as the inhibition of de novo lipogenesis and the initiation of gluconeogenesis in the liver. The transcription factor sterol regulatory element‐binding protein‐1 (SREBP‐1), which plays a critical role in the regulation of lipogenesis, is suppressed during fasting, resulting in the suppression of hepatic lipogenesis. We previously demonstrated that the interaction of fasting‐induced Kruppel‐like factor 15 (KLF15) with liver X receptor serves as the essential mechanism for the nutritional regulation of SREBP‐1 expression. However, the underlying mechanisms of KLF15 induction during fasting remain unclear. In this study, we show that the glucocorticoid receptor (GR) regulates the hepatic expression of KLF15 and, subsequently, lipogenesis through the KLF15‐SREBP‐1 pathway during fasting. KLF15 is necessary for the suppression of SREBP‐1 by GR, as demonstrated through experiments using KLF15 knockout mice. Additionally, we show that GR is involved in the fasting response, with heightened binding to the KLF15 enhancer. It has been widely known that the hypothalamic–pituitary–adrenal (HPA) axis regulates the secretion of glucocorticoids and plays a significant role in the metabolic response to undernutrition. These findings demonstrate the importance of the HPA‐axis‐regulated GR‐KLF15 pathway in the regulation of lipid metabolism in the liver during fasting. [ABSTRACT FROM AUTHOR]

Mast cells are a significant source of cytokines and chemokines that play a role in pathological processes. Gangliosides, which are complex lipids with a sugar chain, are present in all eukaryotic cell membranes and comprise lipid rafts. Ganglioside GM3, the first ganglioside in the synthetic pathway, is a common precursor of the specifying derivatives and is well known for its various functions in biosystems. Mast cells contain high levels of gangliosides; however, the involvement of GM3 in mast cell sensitivity is unclear. Therefore, in this study, we elucidated the role of ganglioside GM3 in mast cells and skin inflammation. GM3 synthase (GM3S)‐deficient mast cells showed cytosolic granule topological changes and hyperactivation upon IgE‐DNP stimulation without affecting proliferation and differentiation. Additionally, inflammatory cytokine levels increased in GM3S‐deficient bone marrow–derived mast cells (BMMC). Furthermore, GM3S‐KO mice and GM3S‐KO BMMC transplantation showed increased skin allergic reactions. Besides mast cell hypersensitivity caused by GM3S deficiency, membrane integrity decreased and GM3 supplementation rescued this loss of membrane integrity. Additionally, GM3S deficiency increased the phosphorylation of p38 mitogen‐activated protein kinase. These results suggest that GM3 increases membrane integrity, leading to the suppression of the p38 signalling pathway in BMMC and contributing to skin allergic reaction. [ABSTRACT FROM AUTHOR]

Female athletes follow a strict diet and perform rigorous exercise to boost their performance, which induces health issues called the female athlete triad (FAT), defined as the combination of disordered eating, amenorrhoea and low bone mineral density. It is known to have a significant effect on bones. However, its effects on the small intestine, which is responsible for nutrient uptake into the body, remain unclear. In this study, we created an animal model of FAT to examine its effects on digestive and absorptive molecules in the small intestine. Thirty 5-week-old female Sprague-Dawley (sd) rats with an initial body weight of about 147 g were divided into control (Con, n = 7), exercise (Ex, n = 7), food restriction (FR, n = 8) and exercise plus food restriction (FAT, n = 8) groups. The rats were subjected to 4 weeks of wheel running (Ex, FAT) and 50–40 % food restriction (FR, FAT) to examine the effects on bone and typical digestive enzymes and transporters in the jejunum. Two-way ANOVA and the Kruskal–Wallis test were used for statistical analysis of normal and non-normal data, respectively. Four weeks of exercise and food restriction decreased bone weight (vs. other group P < 0·01) and bone breaking power (vs. other group P < 0·01). Villus height decreased in the jejunum (vs. other group P < 0·01), but the expression of typical macronutrients digestive enzyme and absorptive molecules remained unchanged. In contrast, sucrase-isomaltase gene (v. Ex P = 0·02) and protein expression were increased (vs. other group P < 0·05). The study findings show that FAT affects sucrase-isomaltase without histone methylation changes. [ABSTRACT FROM AUTHOR]

Although branched-chain amino acids (BCAA) are known to stimulate myofibrillar protein synthesis and affect insulin signaling and kynurenine metabolism (the latter being a metabolite of tryptophan associated with depression and dementia), the effects of BCAA supplementation on type 2 diabetes (T2D) are not clear. Therefore, a 24-week, prospective randomized open blinded-endpoint trial was conducted to evaluate the effects of supplementation of 8 g of BCAA or 7.5 g of soy protein on skeletal muscle and glycemic control as well as adverse events in elderly individuals with T2D. Thirty-six participants were randomly assigned to the BCAA group (n = 21) and the soy protein group (n = 15). Skeletal muscle mass and HbA1c, which were primary endpoints, did not change over time or differ between groups. However, knee extension muscle strength was significantly increased in the soy protein group and showed a tendency to increase in the BCAA group. Homeostasis model assessment for insulin resistance did not significantly change during the trial. Depressive symptoms were significantly improved in the BCAA group but the difference between groups was not significant. Results suggested that BCAA supplementation may not affect skeletal muscle mass and glycemic control and may improve depressive symptoms in elderly individuals with T2D. [ABSTRACT FROM AUTHOR]

In this study, using GK diabetic rats, we compared the effects of three insulin sensitizers on lipid oxidation and the aortic relaxation response. Eight-week-old rats were treated for 4 wk with either troglitazone or pioglitazone, both of which are thiazolidinediones, or with metformin. Despite the fact that only troglitazone has a similarity in structure to [alpha]-tocopherol, a potent antioxidant, the level of thiobarbituric acid-reactive substance was lower, and the lag time of the conjugated dienes was longer, in the blood samples from the rats in both troglitazone- and pioglitazone-treated groups. In contrast, another insulin sensitizer, metformin, failed to inhibit the oxidation of blood samples. The aortic vasorelaxation response was increased in both troglitazone- and metformin-treated groups compared with the untreated group. These findings suggest that thiazolidinediones have a beneficial effect on lipid oxidation irrespective of the drug's structural similarity to [alpha]-tocopherol. It is also suggested that the thiazolidinediones and metformin improve vascular function in diabetes. These effects may play a role in the prevention of atherosclerosis in diabetic patients. diabetes mellitus; low-density lipoprotein; endothelium; Goto-Kakizaki rats

• In aortic valve stenosis (AS) patients referred for transcatheter aortic valve implantation, wall stress did not correlate with plasma B-type natriuretic peptide (BNP) level. • AS and heart failure severities determine plasma BNP level. • BNP release is associated with myocardial damage progression under preserved left ventricular ejection fraction. Brain or B-type natriuretic peptide (BNP) is an objective marker to diagnose the presence of heart failure (HF) and assess its severity. However, the determinants of serum BNP level in elderly patients with severe aortic valve stenosis (AS) referred for transcatheter aortic valve implantation (TAVI) have not been well investigated. We prospectively studied 106 AS patients who underwent TAVI. Cardiac catheterization, transesophageal echocardiography, and blood collection for plasma BNP level measurements were performed simultaneously just before the TAVI procedures. Ninety-nine patients (83.9±5.0 years, 33% male) were studied. The natural logarithm of BNP (lnBNP) level was 5.4±0.9 pg/mL. Significant correlations with lnBNP level were observed in: 1) the history of syncope, prior HF medication, and New York Heart Association class III or IV (R=0.255, p =0.011) (R=0.210, p =0.037) (R=0.402, p <0.001), 2) albumin and hemoglobin level (R=-0.289, p =0.004) (R=0.263, p =0.009), 3) Left ventricular (LV) ejection fraction and global longitudinal strain (LVGLS) (R=-0.338, p <0.001) (R=0.447, p <0.001), 4) LV end-diastolic volume index (EDVI), LV mass index, and left atrial volume index (R=0.280, p =0.005) (R=0.366, p <0.001) (R=0.337, p <0.001), 5) the catheter-measured pressure gradient across the aortic valve (AVPG) (R=0.365, p <0.001). Note that LV wall stress was not significantly correlated with lnBNP level. LVGLS, AVPG, hemoglobin level, and LVEDVI were independently correlated with ln BNP level (R=0.652, LVGLS; β=0.395, p <0.006, AVPG; β=0.291, p =0.001, hemoglobin level; β=-0.216, p =0.011, and LVEDVI; β=0.203, p =0.016, respectively). In severe AS patients candidate for TAVI, multiple factors, including the severities of AS and HF conditions and subclinical LV dysfunction determined by LVGLS affects plasma BNP level. [Display omitted] [ABSTRACT FROM AUTHOR]

Redox-mediated modulation of cysteine (Cys) thiols has roles in various pathophysiological functions. We recently found that formation of disulfide-linked complexes of apolipoprotein (apo) E3 prevented apoE3 from irreversible oxidation. In this report, the influence of modification of Cys thiols in apoE2 and apoE3 on interactions with lipids was investigated. The apoE redox status was examined by a band-shift assay using a maleimide compound, and interactions with lipids were evaluated by a kinetic assay using dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and non-denaturing polyacrylamide gel electrophoresis. A reduction in DMPC clearance activity of apoE2 and apoE3 but not apoE4 was observed. Although hydrogen peroxide-induced oxidation decreased the clearance activity of the isoforms, apoE2 showed the greatest residual activity. Both Cys thiol masking and dimerization decreased the activity of apoE2 and apoE3 but not apoE4. In contrast, apoAII preincubation markedly increased the activity (apoE2 > apoE3 > apoE4), in accordance with the formation of apoE-AII and apoAII-E2-AII complexes. ApoAII preincubation also reduced the particle size of apoE-DMPC liposome complexes, especially for apoE2. Redox-mediated modification of Cys thiols of apoE2 or apoE3, especially disulfide bond formation with apoAII, affects lipid metabolism and consequently may be responsible for the diverse isoform specificity of apoE. [ABSTRACT FROM AUTHOR]

Summary: It is unclear whether γδ T cells are involved in humoral immunity against Plasmodium infection. Here, we show that B‐cell‐immunodeficient mice and γδ T‐cell‐deficient mice were incapable of protecting against Plasmodium berghei XAT parasites. γδ T‐cell‐deficient mice developed reduced levels of antigen‐specific antibodies during the late phase of infection. The numbers of follicular helper T cells and germinal centre B cells in γδ T‐cell‐deficient mice were lower than in wild‐type mice during the late phase of infection. Expression profiling of humoral immunity‐related cytokines in γδ T cells showed that interleukin‐21 (IL‐21) and interferon‐γ (IFN‐γ) are increased during the early stage of infection. Furthermore, blockade of IL‐21 and IFN‐γ signalling during the early stage of infection led to reduction in follicular helper T cells and germinal centre B cells. γδ T‐cell production of IL‐21 and IFN‐γ is crucial for the development and maintenance of follicular helper T cells and germinal centre B cells during the late phase of infection. Our data suggest that γδ T cells modulate humoral immunity against Plasmodium infection. γδ T cells produce interleukin‐21 (IL‐21) and interferon‐γ (IFN‐γ) during the early phase of Plasmodium infection. The γδ T‐cell‐produced IL‐21 and IFN‐γ elicit the development/maintenance of follicular helper T cells and germinal centre B cells during the late phase of Plasmodium infection. [ABSTRACT FROM AUTHOR]