Touko SATO

Background: Maternal diet and sociodemographic factors influence xanthophyll concentration and composition in human milk. However, the importance of dietary patterns regarding the intake of fruits, vegetables, and xanthophylls remains unclear. Objective: The aim was to determine the composition of xanthophylls in the human milk of Japanese mothers and explore associations of xanthophylls with dietary and sociodemographic factors. Methods: This cross-sectional study was conducted in the early phase of the Japanese Human Milk Study. Xanthophyll content was measured using liquid chromatography at 30-36 d postpartum. Maternal intake of foods, nutrients, and dietary supplements was estimated using a food-frequency questionnaire. Linear regression models were established using xanthophylls, maternal diet, and sociodemographic factors. Results: Xanthophyll concentrations were measured in human milk from 118 mothers. The xanthophyll concentration varied among individuals. The median (IQR) concentrations of lutein, zeaxanthin, and β-cryptoxanthin were 65.6 ng/mL (51.6-103.4 ng/mL), 18.6 ng/mL (12.9-25.8 ng/mL), and 15.6 ng/mL (9.0-26.0 ng/mL), respectively. In multivariate models, the lutein concentration was associated independently with dietary green vegetables, exclusive breastfeeding, and education (r 2 = 0.153 for the model; β ± SE: 0.468 ± 0.198, 25.048 ± 10.222, and 13.460 ± 6.774; standardized β = 0.210, 0.217, and 0.175; P = 0.019, 0.016, and 0.049 for dietary green vegetables, exclusive breastfeeding, and education, respectively). For zeaxanthin, exclusive breastfeeding was the most appropriate predictor (r 2 = 0.085; β ± SE: 7.811 ± 3.300; standardized β = 0.218; P = 0.020). The highest predictive power for human milk β-cryptoxanthin was obtained with dietary β-cryptoxanthin (r 2 = 0.258; β ± SE: 0.089 ± 0.015; standardized β = 0.468; P < 0.001), attributed to maternal citrus intake. Conclusions: β-Cryptoxanthin in human milk was the xanthophyll most influenced by the maternal diet in Japanese women. The β-cryptoxanthin concentration in human milk was reflected by the maternal β-cryptoxanthin intake, mainly attributed to Japanese citrus consumption. This trial was registered in the Japanese Clinical Trials Registry (https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017649) as UMIN000015494.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used to reduce hyperglycemia. The present study investigated the effects of a SGLT2 inhibitor, empagliflozin, on hyperglycemia in a novel rat model of non-obesity type 2 diabetes with enlarged kidney (DEK). METHODS: Male DEK rats with non-fasting blood glucose concentrations ≤300 mg/dl and >300 mg/dl were classified as nondiabetic and diabetic, respectively. Groups of nondiabetic (control) and diabetic (DM-cont) rats were fed standard chow for 12 weeks, whereas another group of diabetic (DM-empa) rats was fed standard chow containing empagliflozin (300 mg/kg/day) for 12 weeks. Blood glucose, body weight, glucose tolerance, food and water intake, urinary volume, plasma and urinary biochemical parameters, and bone mineral density were measured, and their kidneys and pancreas histologically analyzed. RESULTS: Treatment with empagliflozin reduced blood glucose concentration and food intake in diabetic rats, but inhibited loss of adeps renis and led to body weight gain. Empagliflozin attenuated polyuria and polydipsia but increased plasma concentrations of total cholesterol, sodium and total protein toward normal level. Empagliflozin also significantly reduced urinary excretion of proteins and electrolytes and restored bone mineral density and plasma concentrations of valine and isoleucine to normal levels. Moreover, dilation of renal tubules and kidney enlargement were not attenuated in the DM-empa group. CONCLUSION: The response of DEK rats to empagliflozin differed from that of other diabetic animal models, suggesting that DEK rats have unique characters for studying and evaluating the multiple biological effects of SGLT2 inhibitors. These findings also indicted that empagliflozin could ameliorate systemic metabolism and improve renal tubule function in diabetic condition.

Information regarding the pharmacokinetics of oral sildenafil in dogs with pulmonary hypertension is limited. In this study, we examined the pharmacokinetics of oral sildenafil in a canine model of chronic embolic pulmonary hypertension (CEPH). The CEPH model was developed by repeatedly injecting microspheres into the pulmonary arteries. The pharmacokinetics of oral sildenafil at 1, 2 and 4 mg/kg was evaluated using four dogs with pulmonary hypertension in the fasted state. The plasma concentrations of sildenafil were determined using high-performance liquid chromatography, and pharmacokinetic parameters were calculated using a noncompartmental analysis. Sildenafil was well tolerated in this study. Proportional increments in the maximum plasma concentration and area under the curve extrapolated to infinity at drug doses of 1, 2 and 4 mg/kg were detected using a power model analysis. No significant differences were observed among the three doses in the time to maximum plasma concentration. The mean residence time and elimination half-life were slightly but significantly higher at a dose of 4 mg/kg than at a dose of 1 mg/kg.

Cancer consists of heterogeneous cells that contain a small population of cells that possess stem cell properties; these cells, referred to as cancer stem cells (CSCs) or tumor-initiating cells, are involved in tumor progression and metastasis. Using a sphere-forming assay, canine mammary CSCs were found to be similar to human breast CSCs. Metabolic reprogramming has been recognized as a hallmark of various cancers. However, the significance of cellular metabolism in CSCs remains unclear. The aim of this study was to define the metabolic characteristics of CSCs derived from canine mammary tumors and gain an understanding of the maintenance of stemness. We identified metabolite profiles of canine mammary adenocarcinoma cell lines using gas chromatography-mass spectrometry. Metabolites were extracted from both adherent and sphere-forming cells derived from three cell lines. Sphere-forming cells were separated from adherent cells using an orthogonal, partial least-squares discriminant analysis. Sphere-forming cells were found to contain high levels of the amino acids alanine, glycine and proline compared with adherent cells. They also had high levels of palmitoleate, palmitate and dihomo-gamma-linolenic acid compared with adherent cells. In a sphere-forming assay, palmitate increased the number of spheres for all cell lines. These results indicate that the sphere-forming cells derived from canine mammary adenocarcinoma cell lines have specific metabolic profiles that may be useful for the development of CSC-specific therapies targeting metabolic pathways and potential stemness biomarkers; these results also clarify the maintenance of stemness in canine mammary CSCs.