Mototada Shichiri

Efficacy of high sodium intake in a boy with instantaneous orthostatic hypotension.

Abstract We report the case of a 14-year-old boy with instantaneous orthostatic hypotension (INOH) with symptoms of orthostatic intolerance. We investigated the effect of high sodium intake on hemodynamics and circulatory responses to orthostatic stress using Portapres. Moreover, a multifrequency bioelectrical impedance method was used to confirm increased plasma volume. Although we began treatment with an alpha-adrenoceptor agonist after his admission into our hospital, the effect was not sufficient. We, therefore, began a regimen of high sodium intake (NaCl 3 g two times a day per os in addition to regular diet, NaCl 5–6 g /day) to increase plasma volume. As a result, 48 hours after sodium intake, orthostatic tolerance was markedly improved with a concomitant increase in blood pressure in the orthostatic test. By measuring the patients body water before and after the high sodium intake, we were able to document the increase in plasma volume. We conclude that high sodium intake is an effective treatment for orthostatic hypotension in combination with vasoactive drugs.

Oleuropein-Rich Diet Attenuates Hyperglycemia and Impaired Glucose Tolerance in Type 2 Diabetes Model Mouse

Oleuropein, a phenolic compound found in abundance in olive leaves, has beneficial effects on various diseases. However, it is unknown whether an oleuropein-rich diet is efficacious against type 2 diabetic phenotypes. In this study, we investigated the effects of the oleuropein-containing supplement OPIACE, whose oleuropein content exceeds 35% (w/w), on the diabetic phenotypes in type 2 diabetes model Tsumura Suzuki Obese Diabetes (TSOD) mouse. TSOD mice were fed OPIACE at 4 weeks of age, i.e., before the TSOD mice exhibited diabetic phenotypes. We revealed that OPIACE attenuated hyperglycemia and impaired glucose tolerance in TSOD mice over the long-term (from 10 to 24 weeks of age) but had no effect on obesity. Furthermore, we demonstrated that OPIACE mildly reduced oxidative stress in TSOD mice by 26.2% and attenuated anxiety-like behavioral abnormality in aged TSOD mice. The results suggest that oleuropein suppresses the progression of type 2 diabetes and diabetes-related behavioral abnormality over the long-term.

A Novel Role for α-Tocopherol Transfer Protein (α-TTP) in Protecting against Chloroquine Toxicity

Background: Chloroquine causes serious toxicity by accumulating in lysosomes. Results: Depletion of α-tocopherol transfer protein caused more severe chloroquine toxicity in both cultured cells and mice. Conclusion: α-Tocopherol transfer protein plays a role in protecting chloroquine toxicity by preventing chloroquine accumulation in the lysosomes. Significance: This study describes a novel mechanism for the clearance of lysosomotropic amines. Chloroquine (CQ) is a widely prescribed anti-malarial agent and is also prescribed to treat autoimmune diseases. Clinical treatment with CQ is often accompanied by serious side effects such as hepatitis and retinopathy. As a weak base, CQ accumulates in intracellular acidic organelles, raises the pH, and induces osmotic swelling and permeabilization of acidic organelles, which account for CQ-induced cytotoxicity. We reported previously that CQ treatment caused α-tocopherol transfer protein (α-TTP), a gene product of familial vitamin E deficiency, to change its location from the cytosol to the surface of acidic organelles. Here we show that α-TTP plays a novel role in protecting against CQ toxicity both in vitro and in vivo. In the presence of CQ, rat hepatoma McARH7777 cells, which do not express α-TTP endogenously, showed more severe cytotoxicity, such as larger vacuolation of acidic organelles and caspase activation, than α-TTP transfectant cells. Similarly, α-TTP knockout mice showed more severe CQ toxicity, such as hepatotoxicity and retinopathy, than wild-type mice. These effects were not ameliorated by vitamin E supplementation. In contrast to bafilomycin A1 treatment, which prevents CQ accumulation in cells by raising the pH of acidic organelles, α-TTP expression prevented CQ accumulation without affecting the pH of acidic organelles. Taken together, our data suggest that α-TTP protects against CQ toxicity by preventing CQ accumulation in acidic organelles through a mechanism distinct from vitamin E transport.

Early diagnosis of type 2 diabetes based on multiple biomarkers and non-invasive indices

We previously reported that type 2 diabetes risk, early impaired glucose tolerance and insulin resistance can be predicted by measuring the fasting levels of certain biomarkers. Here we validated these findings in randomly recruited healthy volunteers (n = 101) based on biomarker expression as well as various non-invasive indices. Weight, body mass index, waist circumference and visceral fat differed between individuals with impaired fasting glucose and/or impaired glucose tolerance, and normal subjects. Fasting plasma levels of glycated hemoglobin, leptin, pro-insulin and retinol binding protein 4 differed between impaired fasting glucose/impaired glucose tolerance and normal subjects group and between newly detected diabetes and normal subjects group. Insulin resistance was correlated with fasting levels of insulin and leptin/adiponectin (r = 0.913); of insulin, retinol binding protein 4 and leptin/adiponectin (r = 0.903); and of insulin, glycated albumin, and leptin/adiponectin (r = 0.913). Type 2 diabetes risk, early impaired glucose tolerance and insulin resistance were predicted with >98% specificity and sensitivity by comparing fasting glucose levels to the estimated Matsuda Index based on fasting levels of insulin, adiponectin and leptin with or without oxidative lineolate metabolites. Non-invasive indices are slightly correlated with glucose tolerance and insulin resistance but do not increase the accuracy of predicting type 2 diabetes risk.

Unregulated Lipid Peroxidation in Neurological Dysfunction

Lipid peroxidation has been the subject of extensive studies focusing on its biochemical mechanisms, dynamics, product analysis, involvement in diseases, inhibition, and biological signaling. Lipid hydroperoxides are formed as major primary products, but they are substrates for various enzymes and they also undergo various secondary reactions. Recently, the biological roles of lipid peroxidation products have received much attention, not only for their pathological mechanisms, but also for their practical clinical applications as biomarkers. Hydroxyoctadecadienoic acid from linoleates, F 2 -isoprostanes from arachidonates, and neuroprostanes from docosahexanoates have been proposed as biomarkers for evaluating oxidative stress in vivo and in oxidative stress-related diseases. Although neurodegenerative disorders have various causes, there is much accumulated evidence to show that oxidative stress is involved in their pathologies. Moreover, the mechanism of reactive oxygen species production differs in each disease. Here, the mechanisms underlying Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and Down syndrome are described.