Yoshinori Kitagawa

Protective Effects of Sesamin against Liver Damage Caused by Alcohol or Carbon Tetrachloride in Rodents

The effects of sesamin, a potent inhibitor of delta 5-desaturase in polyunsaturated fatty acid biosynthesis, on the fatty acid compositions of tissue lipids and liver functions were examined in rodents. When a mixture of sesamin and episesamin (51.1:48.2, w/w) was given to rats at a dietary level of 0.5% for 13 days, the proportions of dihomo-gamma-linolenic acid significantly increased not only in the liver but also in plasma and hemocytes, suggesting an interference with delta 5-desaturation by these lignans. The sesamin preparation at the dietary level of 1% improved changes in various blood parameters of the mouse, such as aspartate aminotransferase and alanine aminotransferase activities, and the concentrations of total cholesterol, triglyceride and total bilirubin, caused by continuous inhalation of ethanol. In addition, sesamin showed a significant protective effect against the accumulation of fat droplets and vacuolar degeneration in the mouse liver, as confirmed on histological examination. Sesamin, at the level of 100 mg/kg body weight, also tended to prevent liver lipid accumulation by carbon tetrachloride in mice. These results indicate that sesamin and a related lignan compound have an ability to improve liver function.

Effect of intranasal administration of Lactobacillus pentosus S-PT84 on influenza virus infection in mice

Lactobacillus pentosus strain S-PT84 isolated from Kyoto pickles enhances splenic natural killer (NK) cell activity and exhibit anti-allergic effects by modulating the Th1/Th2 (T-helper1/T-helper2) balance. In the present study, we investigated whether the immune response could be activated by intranasal administration of S-PT84 in the respiratory immune system and protected against influenza virus infection in mice. When BALB/c mice received intranasal administration of S-PT84 once daily for 3 consecutive days, S-PT84 strongly induced interleukin-12 (IL-12) and gamma interferon (IFN-gamma) production in mediastinal lymph node (MLN) cells. At intranasal infection with influenza virus PR8 (a mouse-adapted H1N1 strain) after S-PT84 treatment, the survival rates of mice improved in a dose-dependent manner, and the titer of influenza virus in bronchoalveolar lavage fluids (BALF) was significantly decreased by S-PT84 administration. Production of IL-12 and alpha-interferon (IFN-alpha) in BALF were significantly higher in mice treated with S-PT84 compared to the control mice. Lung NK activity was also significantly augmented in S-PT84-treated mice. These results suggested that the L. pentosus strain S-PT84 showed inhibitory activity against influenza virus infection.

Short-Term Low Calorie Diet Intervention Reduces Serum Advanced Glycation End Products in Healthy Overweight or Obese Adults

Background: Obesity is a metabolic and cardiovascular risk factor. A low calorie diet (LCD) is one of the treatment modalities for weight loss. Serum advanced glycation end products (AGEs) are linked to increased atherogenicity and inflammation in diseases such as diabetes and renal failure. Obesity has an inflammatory component, but interestingly there are no studies on serum AGE levels in obesity or on the effects of LCD as a therapeutic measure on these markers of glycation. Aim: We hypothesized that weight loss by caloric restriction has a beneficial effect on serum AGE levels. We investigated the prospective effects of a sole LCD intervention for weight loss on serum AGEs in a cohort of overweight and non-morbidly obese but otherwise healthy subjects. Methods: A total of 37 Japanese subjects (30 females, 7 males, mean age 48.2 ± 9.3 years) with a mean BMI of 28.3 ± 3.2 participated in this study. During the intervention period of 2 months, they were placed on an LCD (Diet’s™; 5,023 kJ/day) with meal replacement every dinner. The following data were evaluated pre- and post-intervention: AGEs, BMI, waist circumference, blood pressure, serum glucose, cholesterol, triglycerides, HDL- and LDL- cholesterol. Results and Discussion: After the intervention, BMI levels were clearly reduced by 6.3% (p < 0.001), waist circumference by 5.7% (p < 0.002) and triglycerides by 11.9 % (p < 0.002). At baseline, AGEs levels were 63 ± 11 AU for obese subjects and 63 ± 14 for control subjects (not significant). After intervention, AGEs were reduced by 7.21% (range 0–35%, p < 0.001). The percent change in AGEs was significantly and positively correlated with that of triglycerides (r = 0.42, p < 0.009), waist circumference (r = 0.40, p < 0.011), and BMI (r = 0.42, p < 0.007). We show for the first time that serum AGEs can be reduced by an LCD intervention on weight loss, a change that correlates with the reduction in triglycerides. This may plausibly be a reflection of a reduction in glycation/lipoxidation due to the caloric restriction and its metabolic consequences, or it may be due to the decreased intake of food containing glycotoxins, or a combination of both.

Involvement of heme oxygenase-1 induction via Nrf2/ARE activation in protection against H2O2-induced PC12 cell death by a metabolite of sesamin contained in sesame seeds.

Induction of phase II antioxidant enzymes by activation of Nrf2/ARE (antioxidant response element) signaling has been considered as a promising strategy to combat with oxidative stress-related diseases. In the present study, we tested for potential effects of sesamin, a major lignan contained in sesame seeds, its stereoisomer episesamin, and their metabolites on Nrf2/ARE activation in rat pheochromocytoma PC12 cells. Luciferase reporter assays showed that primary metabolites of sesamin and episesamin, SC-1 and EC-1 were the most potent ARE activators among all tested compounds. SC-1 {(1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane} enhanced nuclear translocation of Nrf2 and up-regulated expression of phase II antioxidant enzymes including heme oxygenase-1 (HO-1). Treatment with SC-1 resulted in increased phosphorylation of p38 MAP kinase and transient increase in intracellular ROS levels. N-acetylcysteine (NAC) treatment abolished p38 phosphorylation as well as HO-1 induction caused by SC-1, indicating that ROS are upstream signals of p38 in Nrf2/ARE activation by SC-1. Furthermore, preconditioning with SC-1 attenuated H(2)O(2)-induced cell death in a dose-dependent manner. Finally, treatment with a HO-1 inhibitor, Zn-protoporphyrin (ZnPP), and overexpression of a dominant-negative mutant of Nrf2 diminished SC-1-mediated neuroprotection. Our results demonstrate that SC-1 is capable of protecting against oxidative stress-induced neuronal cell death in part through induction of HO-1 via Nrf2/ARE activation, suggesting its potential to reduce oxidative stress and ameliorate oxidative stress-related neurodegenerative diseases.

Metabolites of sesamin, a major lignan in sesame seeds, induce neuronal differentiation in PC12 cells through activation of ERK1/2 signaling pathway

Sesamin, a major lignan in sesame seeds, exhibits various health benefits. Here, we investigated effects of sesamin, its stereoisomer episesamin, and their metabolites on neuronal differentiation in rat pheochromocytoma PC12 cells. Among all compounds tested, primary metabolites of sesamin and episesamin, SC-1 and EC-1 {S- and R-epimer of 2-(3,4-methylenedioxyphenyl)-6-(3,4-dihydroxyphenyl)-3,7-dioxabicyclo [3.3.0]octane}, were the most potent to induce neuronal differentiation. SC-1 alone induced neuronal differentiation through extracellular signal-regulated kinase (ERK) 1/2 activation that is essential for nerve growth factor (NGF)-induced neuronal differentiation, as shown by the suppression with MEK1/2 inhibitors, PD98059 and U0126. However, SC-1 did not increase phosphorylation of TrkA, a high-affinity NGF receptor, and a TrkA inhibitor, K252a, did not affect SC-1-induced neuronal differentiation. Furthermore, SC-1 potentiated neuronal differentiation in cells co-treated with NGF, which was associated with enhanced ERK1/2 activation and increased expression of neuronal differentiation markers. Interestingly, when treated with SC-1 and a high dose of NGF, formation of synaptic connections and synaptophysin accumulation at the neurite terminals were markedly enhanced. These results indicate that (1) SC-1 alone induces neuronal differentiation, (2) SC-1 potentiates neuronal differentiation in NGF-treated cells, (3) SC-1 enhances formation of synaptic connections in cells treated with a high dose of NGF, all of which are associated with ERK1/2 activation. It is therefore concluded that SC-1 may promote neuronal differentiation by tapping into the ERK1/2-MAPK (mitogen-activated protein kinase) signaling pathway downstream from the TrkA receptor in PC12 cells.

Genetic polymorphisms of the renin-angiotensin system and obesity-related metabolic changes in response to low-energy diets in obese women

OBJECTIVE Genetic polymorphisms of the renin-angiotensin system have been implicated in cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and 3123C/A polymorphism of the angiotensin II type 2 receptor (AT(2)R) gene affect blood pressure and other obesity-related metabolic changes in response to low-energy diets using meal replacement shakes for weight loss. METHODS Clinical, metabolic, and biochemical profiles were measured before and after a 2-mo intervention in 32 obese women (age 49.9 ± 8.4 [SD] y; BMI 28.4 ± 3.3 kg/m²) restricted to 1200 kcal/d (5021 kJ/d). The polymorphisms were determined with an intercalater-mediated FRET probe assay system. RESULTS Although weight loss and nutrient intake levels did not differ among the genotypes, the reduction in body fat after weight loss was significantly less in the ACE deletion/deletion (D/D) genotype than insertion/insertion (I/I) plus I/D genotype (-2.25 ± 1.40% versus -0.80 ± 1.57%, P < 0.05). The AT₂R A/A group had significantly less improved levels of systolic blood pressure (-7.23 ± 8.50 versus 2.50 ± 12.6 mmHg, P < 0.05), low-density lipoprotein-cholesterol (-0.36 ± 0.29 versus -0.09 ± 0.25 mmol/L, P < 0.05), carbohydrate (-54.4 ± 27.2 versus -31.8 ± 16.3 mg/min, P < 0.05) and fat oxidation (8.31 ± 11.86 versus 0.05 ± 9.99 mg/min, P < 0.05) than the C/C plus C/A genotypes. CONCLUSION The present findings suggest that the homozygous form of the ACE gene may hinder the improvement of body fat and that the homozygous form of the AT₂R gene may make improving systolic blood pressure and some obesity-related metabolic parameters through a dietary intervention difficult among obese women.

Dietary Flavonoids Activate the Constitutive Androstane Receptor (CAR)

The constitutive androstane receptor (CAR) is known as a xeno-sensor that regulates genes involved in xenobiotic excretion and energy metabolism. This study tested a variety of polyphenols for their ability to modulate CAR activity. HepG2 cells were transfected with a CAR expression plasmid and a reporter plasmid containing the human CYP2B6 regulatory region and then treated with flavonoids, catechins, and other bioactive polyphenols. Luciferase assays revealed that baicalein (5,6,7-OH flavone) was a potent activator of both human and mouse CAR. Catechin gallates also activated human and mouse CAR. Wild-type and CAR knockout mice were treated with baicalein and chrysin (5,7-OH flavone), and their liver mRNA was analyzed by real-time polymerase chain reaction (PCR). A significant increase in cyp2b10 mRNA content was observed only in wild-type mice fed chrysin. These results suggest that dietary flavonoids regulate CAR activity and thereby accelerate both detoxification and energy metabolism.

Changes on the physiological lactonase activity of serum paraoxonase 1 by a diet intervention for weight loss in healthy overweight and obese women.

Low caloric diet (LCD) is used for weight loss. Paraoxonase 1 (PON-1) is associated with the antioxidant functions of high-density lipoprotein (HDL). Among limited data on the relationships between obesity and PON-1, there has been no study on the effects of a stand-alone LCD on the physiological lactonase activity of PON-1. We investigated the prospective effects of LCD intervention (2 months) for weight loss on serum PON-1 activities (lactonase, arylesterase [mono-esterase] and tri-esterase) and HDL cholesterol (HDL-C), and their association with low-density lipoprotein cholesterol (LDL-C) in overweight and non-morbidly obese but otherwise healthy women (n = 30; mean age, 50.3 years; mean body mass index [BMI], 28.5 kg/m2). In addition to the data such as BMI, blood pressure, blood glucose and lipids, PON-1 activities were examined between pre- and post-intervention. The intervention reduced all metabolic outcomes, and PON-1 lactonase activity (determined with 5-[thiobutyl]butyrolactone) significantly decreased by 6.1%, paralleled by arylesterase (by 7.3%) and tri-esterase (by 7.8%). In multiple regression analysis, the percent change of PON-1 lactonase was significantly, positively and independently correlated to that of LDL-C (β = 0.51), HDL-C (β = 0.40), and BMI (β = 0.37). Our results showed that the solo diet treatment on weight loss might reduce serum PON-1 lactonase activity with reduced HDL-C and LDL-C. The relationship between the lactonase and LDL-C may be adaptive, plausibly hypothesizing less need for PON-1 activity as an antioxidant property to protect lipoproteins. Further research is needed to confirm this prediction.

Thermoregulatory sympathetic nervous system activity and diet‐induced waist‐circumference reduction in obese Japanese women

The present study is designed to investigate how and to what extent sympathovagal behavior in a balanced low‐calorie diet relates to favorable changes of body mass, waist circumference, and/or metabolic risk factors. The study involved 28 mildly obese women without clinical complications, who underwent an 8‐week calorie restriction program using a 1,200‐kcal daily diet with an adequate nutrient content; including two regular meals, and one formula meal replacement. All subjects were examined before and after the dietary intervention. We measured anthropometric parameters, blood pressure, and biochemical blood profiles for lipid metabolism. Autonomic nervous system activity was evaluated by heart rate variability power spectral analysis. The dietary intervention induced moderate, but significant reduction of waist circumference (−5.3% ± 0.8%), body fat percentage (−5.8% ± 0.8%), and body mass (−6.6% ± 0.5%). Linear regression analysis showed that Δvery low frequency (VLF) power reflecting energy metabolic‐ and thermoregulatory sympathetic function significantly correlated to Δwaist circumference (r = −0.53, P < 0.01), Δbody fat percentage (r = −0.39, P < 0.05), Δbody mass (r = −0.43, P < 0.05), ΔHDL‐cholesterol/total cholesterol ratio (HDL‐C/TC) (r = 0.62, P < 0.001), and Δnonesterified fatty acids (NEFA) (r = 0.56, P < 0.01). A stepwise multiple regression analysis additionally revealed that Δwaist circumference (P = 0.024), ΔHDL‐C/TC (P = 0.013), and ΔNEFA (P = 0.016) were significant and independent factors, which contributing to the variance in ΔVLF power (r2 = 0.61). Although causes and consequences of obesity continue to elude researchers, the present study indicates that thermoregulatory sympathetic activity relates to moderate waist‐circumference reduction together with favorable changes of blood lipid profiles after short‐term dietary modification in mildly obese women. Am. J. Hum. Biol. 2009.

Influence of Lactobacillus pentosus S-PT84 Ingestion on the Mucosal Immunity of Healthy and Salmonella Typhimurium-Infected Mice

Lactobacillus pentosus (L. pentosus) strain S-PT84, isolated from Kyoto pickles, enhances splenic natural killer (NK) cell activity, and has high T-helper1 (Th1) cytokine and type 1-IFN (IFN-α) inducing activity. In the present study, we investigated the influence of S-PT84 ingestion on the mucosal immunity of healthy and Salmonella Typhimurium (S. Typhimurium)-infected mice. In the S. Typhimurium infection model, numbers of S. Typhimurium in feces and the spleen were significantly decreased, and body weight loss and deterioration in the general health score of S. Typhimurium-infected mice were improved by S-PT84 ingestion. Oral administration of S-PT84 enhanced IL-5 and IL-6 production from Peyer’s patch cells in vitro, with a concomitant significant increase in IgA production from Peyer’s patch cells, which may explain the mechanism of enhanced IgA production in the small intestine in vivo. These results suggest that S-PT84 ingestion is useful for the maintenance of health or the improvement of certain symptoms during pathogen infection.