Sayori Wada

A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise

Objective Several epidemiological studies have shown that regular exercise can prevent the onset of colon cancer, although the underlying mechanism is unclear. Myokines are secreted skeletal muscle proteins responsible for some exercise-induced health benefits including metabolic improvement and anti-inflammatory effects in organs. The purpose of this study was to identify new myokines that contribute to the prevention of colon tumorigenesis. Methods To identify novel secreted muscle-derived proteins, DNA microarrays were used to compare the transcriptome of muscle tissue in sedentary and exercised young and old mice. The level of circulating secreted protein acidic and rich in cysteine (SPARC) was measured in mice and humans that performed a single bout of exercise. The effect of SPARC on colon tumorigenesis was examined using SPARC-null mice. The secretion and function of SPARC was examined in culture experiments. Results A single bout of exercise increased the expression and secretion of SPARC in skeletal muscle in both mice and humans. In addition, in an azoxymethane-induced colon cancer mouse model, regular low-intensity exercise significantly reduced the formation of aberrant crypt foci in wild-type mice but not in SPARC-null mice. Furthermore, regular exercise enhanced apoptosis in colon mucosal cells and increased the cleaved forms of caspase-3 and caspase-8 in wild-type mice but not in SPARC-null mice. Culture experiments showed that SPARC secretion from myocytes was induced by cyclic stretch and inhibited proliferation with apoptotic effect of colon cancer cells. Conclusions These findings suggest that exercise stimulates SPARC secretion from muscle tissues and that SPARC inhibits colon tumorigenesis by increasing apoptosis.

Chemoprevention of Tocotrienols: The Mechanism of Antiproliferative Effects

Tocotrienols have been reported as antitumor agents and widely commercialized as an antioxidant dietary supplement. Tocotrienols have more significant biological activity than tocopherols, although serum level of tocotrienols is much lower than that of tocopherols. This may be because intracellular concentration of tocotrienols was revealed to be significantly higher compared with tocopherols, and tocotrienol accumulation is observed in tumor. Previous reports have suggested antiproliferative effect, induction of apoptosis, modulation of cell cycle, antioxidant activity, inhibition of angiogenesis, and suppression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity as anticarcinogenesis mechanisms of tocotrienols both in vivo and in vitro. Extension of the duration of host survival was observed in tumor-implanted mice treated with tocotrienol. Tocotrienols induce apoptosis mainly via mitochondria-mediated pathway. Cell cycle arrest is due to suppression of cyclin D by tocotrienols. Tocotrienols also inhibit vascularization-reducing proliferation, migration and tube formation. Malignant proliferation demands elevation of HMG CoA reductase activity, and tocotrienols suppress its activity. Tocotrienol treatment decreases oncogene expression and increases the level of tumor suppressors. Only a few clinical trials to determine the effects of tocotrienol on cancer prevention or treatment have been carried out. There is no convincing or probable evidence of the role of tocotrienols in cancer prevention, while alpha-tocopherol has been suggested to have a limited anti-prostate cancer potential. Neither beneficial activity nor adverse effect of tocotrienol has sufficiently been explored so far. The above-mentioned mechanisms of tocotrienols seem to be promising for cancer prevention; however, further clinical studies are warranted to assess the efficacy and safety of tocotrienol.

Ingestion of low dose pyroglutamyl leucine improves dextran sulfate sodium-induced colitis and intestinal microbiota in mice.

Inflammatory bowel diseases (IBD) are based on chronic inflammation in the gastrointestinal tract. We previously found anti-inflammatory peptide pyroGlu-Leu in the enzymatic hydrolysate of wheat gluten. The objective of present study is to elucidate improvement of colitis by oral administration of pyroGlu-Leu in an animal model. Acute colitis was induced by dextran sulfate sodium (DSS), and various concentrations of pyroGlu-Leu were administrated by oral gavage for 7 days. A dose of 0.1 mg/kg body weight/day showed the most significant improvement. The pyroGlu-Leu concentration was significantly increased 24 h after oral administration both in the small intestine and the colon compared with the baseline. It was 20-fold higher in the small intestine than the colon. Administration of pyroGlu-Leu normalized population of Bacteroidetes and Firmicutes in the colon. These results indicate that pyroGlu-Leu has a potential therapeutic effect against IBD at a practical dose.

Assessment of Daily Food and Nutrient Intake in Japanese Type 2 Diabetes Mellitus Patients Using Dietary Reference Intakes

Medical nutrition therapy for the management of diabetes plays an important role in preventing diabetes complications and managing metabolic control. However, little is known about actual eating habits of individuals with type 2 diabetic mellitus (T2DM), especially in Japan. Therefore, we sought to (1) assess the dietary intake of individuals with T2DM, and (2) characterize their intake relative to national recommendations. This cross-sectional study involved 149 patients (77 males and 72 females) aged 40–79 years with T2DM recruited at a Kyoto hospital. Dietary intake was assessed using a validated self-administered diet history questionnaire. Under-consumption, adequacy, and over-consumption, of nutrients were compared to the age- and sex-based standards of the Japanese Dietary Reference Intakes. Among the results, most notable are (1) the inadequacy of diets in men with respect to intake of vitamins and minerals, likely owing to low intake of vegetables and fruits; (2) excess contributions of fat intake to total energy in both sexes; and (3) excess consumption of sweets and beverages relative to the national average. The prevalence of diabetes complications may be increasing because of a major gap between the typical dietary intake of individuals with T2DM and dietary recommendation.

Dietary Intervention with Cooking Instructions and Self-monitoring of the Diet in Free-Living Hypertensive Men

The control of blood pressure (BP) is important in the prevention of cardiovascular diseases. This study was conducted to evaluate the effect of a dietary educational program for free-living, high-normal, and stage 1 or 2 hypertensive men. The participants were volunteers aged 40–75 years who agreed to the intervention. They were divided into two groups: 39 men for the intervention group and 32 men for the control group. BP, urinary sodium and potassium excretion, dietary and lifestyle data, and nonfasting venous blood sample were collected at baseline and after the intervention period. The intervention was designed to decrease sodium level with an emphasis on a decrease in the consumption of salted foods and to increase potassium level with an emphasis on an increase in the consumption of fruit and vegetables through cooking instructions and self-monitoring of the diet. At the baseline, there were no significant differences observed between the groups, except the diastolic BP. In the intervention group, a greater decrease in the urinary sodium-to-potassium excretion ratio was observed, compared with the control group (net difference 0.6, P = .029). The systolic and diastolic BP (mm Hg) decreased in the intervention group (149.0–143.0, P = .073; 93.0–87.0, P = .002), but no changes were observed in the control group (145.0–143.0, P = .231; 84.9–85.3, P = .381). In the intervention group, the urinary sodium-to-potassium excretion ratio was significantly improved by focusing on cooking instructions and self-monitoring of the diet.

Combined light exercise after meal intake suppresses postprandial serum triglyceride.

PURPOSE The effect of exercise performed on the day of meal intake on postprandial triglyceride concentration, which is an independent risk factor for cardiovascular disease, is unclear. The present study investigated the effects of combined low-intensity exercise before and after a high-fat meal on serum triglyceride concentrations. METHODS Ten healthy young subjects (four men and six women) consumed a relatively high-fat diet (fat energy ratio: men = 37.8%, women = 39.1%). In the exercise trials, subjects performed brisk walking (2.0 km) after light resistance exercise, either 60 min before or after meal intake. Blood samples were collected before and 2, 4, and 6 h after meal intake. RESULTS Exercise resulted in a reduction in the transient elevation in serum triglyceride concentration observed 2 h after meal intake in the postmeal trial (131 ± 67 mg·dL) when compared with the sedentary trial (172 ± 71 mg·dL; 95% confidence interval = 7.2-79.4, d = -1.00). This was also observed in the premeal trial, although the effect was less pronounced (148 ± 66 mg·dL; 95% confidence interval = -9.0 to 59.0, d = -0.57). The triglyceride concentrations in the VLDL, LDL, and HDL fractions, but not the chylomicron fraction, were also decreased 2 h after meal intake in both exercise trials, whereas the integrated triglyceride values after meal intake showed a greater decrease when exercise was performed after meal intake (d = -1.23) than before (d = -0.47). The concentration of serum growth hormone was drastically increased after exercise in both trials. CONCLUSIONS Low-intensity exercise on the day of meal intake, particular after intake, can prevent the elevation of postprandial triglyceride concentration in healthy young subjects.

Chronic inflammation-derived nitric oxide causes conversion of human colonic adenoma cells into adenocarcinoma cells.

It has been suggested that nitric oxide (NO) derived from chronically inflamed tissues is a cause of carcinogenesis. We herein demonstrated that administration of an inducible NO synthase inhibitor, aminoguanidine, significantly suppressed the tumorigenic conversion of human colonic adenoma (FPCK-1-1) cells into adenocarcinoma (FPCK/Inflam) cells accelerated by foreign body-induced chronic inflammation in nude mice. To determine whether NO directly promotes carcinogenesis, we exposed FPCK-1-1 cells continuously to chemically generated NO (FPCK/NO), and periodically examined their tumorigenicity. FPCK/NO cells formed tumors, whereas vehicle-treated cells (FPCK/NaOH) did not. We selected a tumorigenic population from FPCK/NO cells kept it in three-dimensional (3D) culture where in vivo-like multicellular spheroidal growth was expected. FPCK/Inflam cells developed large spheroids whereas FPCK/NO cells formed tiny but growing compact aggregates in 3D culture. Meanwhile, FPCK-1-1 and FPCK/NaOH cells underwent anoikis (apoptotic cell death consequential on insufficient cell-to-substrate interactions) through activation of caspase 3. The survived cells in the 3D culture (FPCK/NO/3D), which were derived from FPCK/NO cells, showed a similar tumor incidence to that of FPCK/Inflam cells. These results showed that NO was one of the causative factors for the acceleration of colon carcinogenesis, especially in the conversion from adenoma to adenocarcinoma in the chronic inflammatory environment.

Suppression of SERPINA1-albumin complex formation by galectin-3 overexpression leads to paracrine growth promotion of chronic myelogenous leukemia cells

Galectin-3 is induced in chronic myelogenous leukemia (CML) cells by co-culture with bone marrow stromal cells, making paracrine growth promotion of CML cells in conditioned medium (CM) from galectin-3 overexpressing CML cells more potent. We used gel filtration chromatography to demonstrate that the bovine SERPINA1-fetal bovine serum albumin (BSA) complex was specifically suppressed in CM from galectin-3 overexpressing cells. The SERPINA1-BSA complex as well as human plasma SERPINA1 inhibited the growth of CML cells, while exogenous galectin-3 partly offset this effect. These findings suggest that galectin-3 overexpression promotes paracrine growth of CML cells by interfering with the action of the growth inhibitory SERPINA1-albumin complex.

Loss of p53 in stromal fibroblasts enhances tumor cell proliferation through nitric-oxide-mediated cyclooxygenase 2 activation

Abstract Overexpression of cyclooxygenase 2 (COX-2) by stromal fibroblasts plays a critical role in the early stage of carcinogenesis. COX-2 expression is thought to be positively or negatively regulated by inflammatory chemical mediators or tumor suppressors. In this study, the contributions of inducible nitric oxide synthase (iNOS) and p53 to COX-2 expression were examined using mouse embryonic fibroblasts (MEFs) from wild-type, p53-deficient, iNOS-deficient, and p53/iNOS-deficient mice. These MEFs were treated with 1 μg/mL of lipopolysaccharide and 100 IU/mL of interferon gamma for up to 72 h. iNOS and COX-2 expression were analyzed by Western blotting. iNOS was induced earlier (16 h) in p53-deficient MEFs than in wild-type MEFs (48 h). Elevated expression of COX-2 was sustained for a longer duration in the p53-deficient MEFs. In contrast, COX-2 expression was reduced earlier in the iNOS-deficient MEFs. Addition of an exogenous NO donor (0.8 mM of S-nitroso-l-glutathione) to the iNOS-deficient MEFs augmented COX-2 expression. Co-culture with stimulated p53-deficient MEFs promoted cell proliferation of mouse rectal polyploid carcinoma CMT93 cells, but treatment with a COX-2-specific inhibitor counteracted this effect. These results suggest that loss of function of the p53 gene in stromal fibroblasts enhances COX-2 expression by enhancing iNOS expression and the resultant production of NO, contributing to the promotion of tumor growth.

Lower vegetable protein intake and higher dietary acid load associated with lower carbohydrate intake are risk factors for metabolic syndrome in patients with type 2 diabetes: Post-hoc analysis of a cross-sectional study

A low‐carbohydrate diet based on animal sources is associated with higher all‐cause mortality, whereas a vegetable‐based low‐carbohydrate diet is associated with lower cardiovascular disease mortality. It has been suggested that acid/base imbalance might play an important role in some cardiometabolic abnormalities. The aims of the present study were to evaluate whether carbohydrate intake is associated with quality of dietary protein and acid load, and whether these are related to metabolic syndrome in patients with type 2 diabetes.