Nanako Aki

Singlet oxygen induced products of linoleates, 10- and 12-(Z,E)-hydroxyoctadecadienoic acids (HODE), can be potential biomarkers for early detection of type 2 diabetes.

Current diagnostic tests such as glycemic indicators have limitations for early detection of impaired glucose tolerance (IGT), which leads to diabetes. Oxidative stress induced by various oxidants in a random and destructive manner is considered to play an important role in the pathophysiology of a number of human disorders and diseases such as impaired glucose tolerance. We have developed an improved method for the measurement of in vivo lipid peroxidation, where the presence of 8-iso-prostaglandin F2α (8-iso-PGF2α), hydroxyoctadecadienoic acids (HODEs), hydroxyeicosatetraenoic acids (HETEs), and 7-hydroxycholesterol (7-OHCh), as well as their parent molecules, linoleic acid (LA) and cholesterol (Ch), was determined by performing LC-MS/MS (for 8-iso-PGF2α, HODE, and HETE) and GC-MS (for 7-OHCh, LA, and Ch) after reduction with triphenyl phosphine and saponification by potassium hydroxide. We then applied this method to volunteers (n = 57), including normal type (n = 43), “high-normal” (fasting plasma glucose, 100–109 mg/dL, n = 7), pre-diabetic type (IGT, n = 5), and diabetic type (n = 2) subjects who are diagnosed by performing oral glucose tolerance tests (OGTTs). Several biomarkers in plasma, such as insulin, leptin, adiponectin, interleukin-6, tumor necrosis factor-α, high sensitivity-C-reactive protein, HbA1c, and glucose levels were measured during OGTT. We found that the fasting levels of (10- and 12-(Z,E)- HODE)/LA increased significantly with increasing levels of HbA1c and glucose during OGTT and with insulin secretion and resistance index. In conclusion, 10- and 12-(Z,E)-HODE may be prominent biomarkers for the early detection of IGT and “high-normal” type without OGTT.

Palmitate-Stimulated Monocytes Induce Adhesion Molecule Expression in Endothelial Cells via IL-1 Signaling Pathway

Increased intake of saturated fatty acids (SFAs), such as palmitate (Pal), is linked to a higher risk of type 2 diabetes and cardiovascular disease. Although recent studies have investigated the direct effects of SFAs on inflammatory responses in vascular endothelial cells, it remains unknown whether SFAs also induce these responses mediated by circulating cells. In this study, especially focused on adhesion molecules and monocytes, we investigated the indirect effects of Pal on expression and release of ICAM‐1 and E‐selectin in vascular endothelial cells. Phorbol 12‐myristate 13‐acetate (PMA)‐treated THP‐1 (pTHP‐1) cells and human monocytes were stimulated with various free fatty acids (FFAs). SFAs, but not unsaturated fatty acids (UFAs), increased interleukin (IL)‐1β secretion and decreased IL‐1 receptor antagonist (IL‐1Ra) secretion, resulting in an increase in the IL‐1β/IL‐1Ra secretion ratio. UFAs dose‐dependently inhibited the increase in IL‐1β secretion and decrease in IL‐1Ra secretion induced by Pal. Moreover, in human aortic and vein endothelial cells, expression and release of ICAM‐1 and E‐selectin were induced by treatment with conditioned medium collected from Pal‐stimulated pTHP‐1 cells and human monocytes, but not by Pal itself. The up‐regulated expression and release of adhesion molecules by the conditioned medium were mostly abolished by recombinant human IL‐1Ra supplementation. These results suggest that the Pal‐induced increase in the ratio of IL‐1β/IL‐1Ra secretion in monocytes up‐regulates endothelial adhesion molecules, which could enhance leukocyte adhesion to endothelium. This study provides further evidence that IL‐1β neutralization through receptor antagonism may be useful for preventing the onset and development of cardiovascular disease. J. Cell. Physiol. 230: 732–742, 2015.

Effects of Free Fatty Acids on Human Salivary Gland Epithelial Cells

Obesity and type 2 diabetes (T2D) are characterized by decreased insulin sensitivity and higher concentrations of free fatty acids (FFAs) in plasma. Among FFAs, saturated fatty acids (SFAs), such as palmitate, have been proposed to promote inflammatory responses. Primary Sjögren’s syndrome (SS) is an autoimmune disease characterized by inflammatory mononuclear cell infiltration and destruction of epithelial cells in the salivary and lacrimal glands. IL-6 production and α-fodrin degradation are increased in salivary gland epithelial cells of patients with primary SS. Although previous studies have shown a link between SS and either dyslipidemia or T2D, little is known about the clinical significance of FFAs in primary SS. Here we report that SFAs, but not unsaturated fatty acids, induced IL-6 production via NF-κB and p38 MAPK activation in human salivary gland epithelial cells. Moreover, palmitate induced apoptosis and α-fodrin degradation by caspase-3 activation. Unlike salivary gland epithelial cells, induction of IL-6 production and the degradation of α-fodrin in response to palmitate were undetectable in squamous carcinoma cells and keratinocytes. Taken together, SFAs induced IL-6 production and α-fodrin degradation in salivary gland epithelial cells, implicating a potential link between the pathogenesis of primary SS and SFAs level in plasma.

Cut-Off Value of Total Adiponectin for Managing Risk of Developing Metabolic Syndrome in Male Japanese Workers

Aim To determine the optimal cut-off value of serum total adiponectin for managing the risk of developing metabolic syndrome (MetS) in male Japanese workers. Methods A total of 365 subjects without MetS aged 20–60 years were followed up prospectively for a mean of 3.1 years. The accelerated failure-time model was used to estimate time ratio (TR) and cut-off value for developing MetS. Results During follow-up, 45 subjects developed MetS. Age-adjusted TR significantly declined with decreasing total adiponectin level (≤ 4.9, 5.0–6.6, 6.7–8.8 and ≥ 8.9 μg/ml, P for trend = 0.003). In multivariate analyses, TR of MetS was 0.12 (95% CI 0.02–0.78; P = 0.03) in subjects with total adiponectin level of 5.0–6.6 μg/ml, and 0.15 (95% CI 0.02–0.97; P = 0.047) in subjects with total adiponectin level ≤ 4.9 μg/ml compared with those with total adiponectin level ≥ 8.9 μg/ml. The accelerated failure-time model showed that the optimal cut-off value of total adiponectin for managing the risk of developing MetS was 6.2 μg/ml. In the multivariate-adjusted model, the mean time to the development of MetS was 78% shorter for total adiponectin level ≤ 6.2 μg/ml compared with > 6.2 μg/ml (TR 0.22, 95% CI: 0.08–0.64, P = 0.005). Conclusion Our findings suggest that the cut-off value for managing the risk of developing MetS is 6.2 μg/ml in male Japanese workers. Subjects with total adiponectin level ≤ 6.2 μg/ml developed MetS more rapidly than did those with total adiponectin level > 6.2 μg/ml.

Associations between intake of dietary fermented soy food and concentrations of inflammatory markers: a cross‐sectional study in Japanese workers

Epidemiological investigations have shown that consumption of soybeans or soy foods reduces the risk of the development of cardiovascular disease, cancer and osteoporosis. The aim of this study was to determine the associations between different soy foods and inflammatory markers, including high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, and IL-18, in Japanese workers. The cross-sectional study included 1,426 Japanese workers (1,053 men and 373 women) aged 20 to 64 years. Intake of 12 soy foods was estimated by a validated food frequency questionnaire. Associations of total soy foods, fermented soy food, non-fermented soy food, soy isoflavone with hs-CRP, IL-6, and IL-18 levels were examined by general linear model regression analysis. We found that total fermented soy food intake was inversely associated with multivariable-adjusted geometric concentration of IL-6 in men (Q1:1.03 pg/mL, Q5:0.94 pg /mL;P for trend = 0.031). Furthermore, it was shown that IL-6 concentrations were inversely associated with miso intake (β = -0.068;p = 0.034) and soy sauce intake in men (β = -0.074;p = 0.018). This study suggests that intake of total fermented soy food, miso and soy sauce be associated with IL-6 concentrations in Japanese men. J. Med. Invest. 65:74-80, February, 2018.

High Levels of Saturated Fatty Acids may Exacerbate the Pathogenesis of Primary Sjögren’s Syndrome

Obesity and type 2 diabetes (T2D) are characterized by decreased insulin sensitivity and higher concentrations of free fatty acids (FFAs) in the serum. Among FFAs, saturated fatty acids, such as palmitate, have been reported to play a role in obesity-associated inflammation. Primary Sjogren’s syndrome (SS) is an autoimmune disease characterized by infiltration of inflammatory mononuclear cells and destruction of epithelial cells in salivary and lacrimal glands. Although epidemiological studies have suggested a link between primary SS and dyslipidemia or T2D, little is known about the clinical significance of elevated serum level of FFAs in primary SS. In salivary gland epithelial cells of patients with primary SS, interleukin (IL)-6 production and α-fodrin degradation are increased. IL-6 is one of the pro-inflammatory cytokines, and the cleavaged α-fodrin serves as an auto-antigen. In this study, we demonstrate that palmitate, but not unsaturated fatty acids, induces IL-6 production and α-fodrin degradation in human salivary gland epithelial cell lines. However, palmitate did not induce these responses in keratinocytes. Taken together, these results suggest that higher levels of saturated fatty acids may promote the severity of primary SS.