Serum Anti-Apo B Antibody Level as Residual CVD Marker in DM Patients under Statin Treatment.

AIM: In the pathogenesis of atherosclerosis, autoantibodies have two-facedness of progression and protection. Previous reports have indicated that low autoantibody levels against apolipoprotein B-100 (apo B-100) could increase the risk of atherosclerotic cardiovascular diseases (CVD) in healthy subjects. In this study, we investigated the relationship between circulating anti-apo B-100 autoantibodies and the clinical parameters in Japanese diabetic patients with or without CVD. METHODS: We measured the serum levels of anti-apo B-100 autoantibodies against native and malondialdehyde (MDA)-modified p45 or p210 epitopes, as well as anti-apo E autoantibodies, using enzyme-linked immunosorbent assay. RESULTS: In patients with CVD, the circulating levels of IgG against native p45, MDA-modified p45, and MDA-modified p210 (IgGN-45, IgGMDA-45, and IgGMDA-210) were significantly lower than those in patients without CVD, whereas no difference was observed in anti-apo E autoantibody levels. In addition, IgMN-45, IgMMDA-45, and IgGMDA-45 were negatively correlated with LDL-C levels, whereas IgGN-45 and IgGN-210 were positively correlated with HbA1c levels. No correlation was observed between autoantibody levels and diabetic microangiopathy. In the statin-treated subgroup, IgGMDA-45 and IgGMDA-210 were significantly lower in patients with CVD than in those without CVD. CONCLUSION: Measurement of serum anti-apo B-100 autoantibodies can be useful for the evaluation of CVD risk in patients with diabetes receiving statin treatment.

An essential role for functional lysosomes in ferroptosis of cancer cells.

Pharmacological challenges to oncogenic Ras-expressing cancer cells have shown a novel type of cell death, ferroptosis, which requires intracellular iron. In the present study, we assessed ferroptosis following treatment of human fibrosarcoma HT1080 cells with several inhibitors of lysosomal activity and found that they prevented cell death induced by the ferroptosis-inducing compounds erastin and RSL3. Fluorescent analyses with a reactive oxygen species (ROS) sensor revealed constitutive generation of ROS in lysosomes, and treatment with lysosome inhibitors decreased both lysosomal ROS and a ferroptotic cell-death-associated ROS burst. These inhibitors partially prevented intracellular iron provision by attenuating intracellular transport of transferrin or autophagic degradation of ferritin. Furthermore, analyses with a fluorescent sensor that detects oxidative changes in cell membranes revealed that formation of lipid ROS in perinuclear compartments probably represented an early event in ferroptosis. These results suggest that lysosomal activity is involved in lipid ROS-mediated ferroptotic cell death through regulation of cellular iron equilibria and ROS generation.

Association of variation range in glycated albumin (GA) with increase but not decrease in plasma glucose: implication for the mechanism by which GA reflects glycemic excursion.

OBJECTIVES: HbA1c mainly reflects mean plasma glucose (PG), whereas glycated albumin (GA) reflects glycemic excursion in addition to mean PG; the mechanism of the difference between HbA1c and GA is unknown. We hypothesized that a transient increase in PG irreversibly produces stable GA unlike HbA1c. To prove this hypothesis, we investigated diurnal variations in PG, HbA1c, #C fraction (a fraction containing unstable HbA1c and modified hemoglobin on HPLC) and GA in diabetic patients. DESIGN AND METHODS: Sixteen diabetic patients with poor glycemic control were enrolled in this study. Blood sampling was performed before and after each meal, before bedtime, and before breakfast on the following day; PG, HbA1c, #C fraction, and GA were measured. The variations of these indicators were compared with those in PG. RESULTS: HbA1c showed almost no change regardless of diurnal glycemic variation. Variation range in #C fraction significantly correlated with variation range in PG when PG increased (R=0.746, p<0.0001) and decreased (R=0.271, p=0.035). On the other hand, variation range in GA significantly correlated with variation range in PG when PG increased (R=0.322, p=0.021), but not when PG decreased (R=0.090, p=0.493). CONCLUSIONS: We observed that variation range in GA significantly correlated with variation range in PG when PG increased but not when PG decreased for the first time. It is considered that GA reflects glycemic excursion through this phenomenon.

Heavy metal adsorptivity of calcium-alginate-modified diethylenetriamine-silica gel and its application to a flow analytical system using flame atomic absorption spectrometry.

This study aimed to evaluate the heavy metal adsorptivity of calcium-alginate-modified diethylenetriamine-silica gel (CaAD) and incorporate this biosorbent into a flow analytical system for heavy metal ions using flame atomic absorption spectrometry (FAAS). The biosorbent was synthesized by electrostatically coating calcium alginate onto diethylenetriamine (dien)-silica gel. Copper ion adsorption tests by a batch method showed that CaAD exhibited a higher adsorption rate compared with other biosorbents despite its low maximum adsorption capacity. Next, CaAD was packed into a 1mL microcolumn, which was connected to a flow analytical system equipped with an FAAS instrument. The flow system quantitatively adsorbed heavy metals and enriched their concentrations. This quantitative adsorption was achieved for pH 3-4 solutions containing 1.0×10(-6) M of heavy metal ions at a flow rate of 5.0 mL min(-1). Furthermore, the metal ions were successfully desorbed from CaAD at low nitric acid concentrations (0.05-0.15 M) than from the polyaminecarboxylic acid chelating resin (Chelex 100). Therefore, CaAD may be considered as a biosorbent that quickly adsorbs and easily desorbs analyte metal ions. In addition, the flow system enhanced the concentrations of heavy metals such as Cu(2+), Zn(2+), and Pb(2+) by 50-fold. This new enrichment system successfully performed the separation and determination of Cu(2+) (5.0×10(-8)M) and Zn(2+) (5.7×10(-8) M) in a river water sample and Pb(2+) (3.8×10(-9) M) in a ground water sample.

Interleukin-6 enhances glucose-stimulated insulin secretion from pancreatic beta-cells: potential involvement of the PLC-IP3-dependent pathway.

OBJECTIVE: Interleukin-6 (IL-6) has a significant impact on glucose metabolism. However, the effects of IL-6 on insulin secretion from pancreatic ß-cells are controversial. Therefore, we analyzed IL-6 effects on pancreatic ß-cell functions both in vivo and in vitro. RESEARCH DESIGN AND METHODS: First, to examine the effects of IL-6 on in vivo insulin secretion, we expressed IL-6 in the livers of mice using the adenoviral gene transfer system. In addition, using both MIN-6 cells, a murine ß-cell line, and pancreatic islets isolated from mice, we analyzed the in vitro effects of IL-6 pretreatment on insulin secretion. Furthermore, using pharmacological inhibitors and small interfering RNAs, we studied the intracellular signaling pathway through which IL-6 may affect insulin secretion from MIN-6 cells. RESULTS: Hepatic IL-6 expression raised circulating IL-6 and improved glucose tolerance due to enhancement of glucose stimulated-insulin secretion (GSIS). In addition, in both isolated pancreatic islets and MIN-6 cells, 24-h pretreatment with IL-6 significantly enhanced GSIS. Furthermore, pretreatment of MIN-6 cells with phospholipase C (PLC) inhibitors with different mechanisms of action, U-73122 and neomycin, and knockdowns of the IL-6 receptor and PLC-ß(1), but not with a protein kinase A inhibitor, H-89, inhibited IL-6-induced enhancement of GSIS. An inositol triphosphate (IP(3)) receptor antagonist, Xestospondin C, also abrogated the GSIS enhancement induced by IL-6. CONCLUSIONS: The results obtained from both in vivo and in vitro experiments strongly suggest that IL-6 acts directly on pancreatic ß-cells and enhances GSIS. The PLC-IP(3)-dependent pathway is likely to be involved in IL-6-mediated enhancements of GSIS.

Regulation of pancreatic beta cell mass by neuronal signals from the liver.

Metabolic regulation in mammals requires communication between multiple organs and tissues. The rise in the incidence of obesity and associated metabolic disorders, including type 2 diabetes, has renewed interest in interorgan communication. We used mouse models to explore the mechanism whereby obesity enhances pancreatic beta cell mass, pathophysiological compensation for insulin resistance. We found that hepatic activation of extracellular regulated kinase (ERK) signaling induced pancreatic beta cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased beta cell mass and normalized serum glucose levels. Thus, interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes.

Relationship between personality and self-measured blood pressure value at home: the Ohasama study.

We conducted a cross-sectional community survey in northern Japan to assess the relationship between personality and home blood pressure value. The Japanese version of the short-form Eysenck personality questionnaire was used to assess personality. A total of 999 people selected from the general population participated. We showed that the personality extroversion score positively affected the systolic blood pressure value, whereas no significant relationship was observed between personality psychoticism or neuroticism and blood pressure value. This study is the first to clarify the relationship between personality assessed by the Eysenck personality questionnaire and blood pressure measured in a non-medical setting. When physicians investigate the pathogenesis of essential hypertension, they should take psychological factors into consideration, as well as the many environmental and genetic factors.