Light-intensity exercise improves memory dysfunction with the restoration of hippocampal MCT2 and miRNAs in type 2 diabetic mice.

Cognitive decline associated with type 2 diabetes mellitus (T2DM) is a risk factor to impair human health. Although light-intensity exercise prevents hippocampal memory dysfunction in pre-symptomatic T2DM animals by altering hippocampal lactate transport and neurotrophic factors, the effects of light-intensity exercise in an advanced stage of T2DM animals remain unclear. Here, ob/ob mice, an animal model of T2DM, were subjected to light-intensity exercise (5.0 m/min) for 30 min/day, five days/week for four weeks. The effects of light-intensity exercise on hippocampal complications, mRNA expressions of monocarboxylate transporter (MCT), and miRNA levels were assessed. The light-intensity exercise improved hippocampal memory retention in ob/ob mice. Downregulated hippocampal Mct2 mRNA levels in T2DM were improved with light-intensity exercise. Hippocampal mRNA levels of Mct1 and Mct4 were unchanged within groups. Based on miRNA sequencing, sedentary ob/ob mice exhibited that 71 miRNAs were upregulated, and 77 miRNAs were downregulated in the hippocampus. In addition, the exercise significantly increased 24 miRNAs and decreased 4 miRNAs in the T2DM hippocampus. The exercise reversed T2DM-induced alterations of hippocampal 9 miRNAs, including miR-200a-3p. Our findings imply that miR-200a-3p/Mct2 in the hippocampus would be a possible clinical target for treating T2DM-induced memory dysfunction.

Physical activity associates empathy in Japanese young adults with specific gene variations of oxytocin receptor and vasopressin V1B receptor.

BACKGROUND: Empathy, consisting of cognitive empathy and affective empathy, is essential for creating relationships with others. Since the genetic polymorphism of oxytocin receptor (OXTR) and arginine-vasopressin V1B receptor (AVPR1B) relate to prosocial behavior and empathy, it would need to innovate strategies for treating human empathy by considering individual genetic variations. Physical activity is expected as a possible strategy; here, we investigated the influences of genetic polymorphisms in OXTR SNP rs53576 and AVPR1B SNP rs28373064, on the relationships of self-reported empathy with physical activity. METHODS: The saliva is collected from a hundred Japanese college students for determining the individual polymorphism of OXTR SNP rs53576 (AA, AG, or GG genotype) and AVPR1B SNP rs28373064 (TT, TC, or CC genotype). In addition, the participants' self-reported cognitive and affective empathy, amounts of physical activity, and sitting time were evaluated with questionaries. RESULTS: The participants with OXTR SNP rs53576 GG genotype showed a significant negative correlation between sitting time and cognitive empathy adjusted by age, gender, and sports experience. Further, there was a trend to correlate between physical activity amounts and cognitive empathy in the participants carrying the G variant in OXTR SNP rs53576 (AG or GG). As for AVPR1B SNP rs28373064, the persons with TT genotype exhibited a negative correlation trend between sitting time and cognitive empathy. CONCLUSIONS: There are possible correlations between the self-reported cognitive empathy and physical activity amounts in the persons carrying the G variant of OXTR rs53576 or with the TT genotype for AVPR1B SNP rs28373064.

Four weeks of light-intensity exercise enhances empathic behavior in mice: The possible involvement of BDNF.

Empathy is one of the essential functions of mammals for maintaining relationships with others. Physical activity contributes to enhancing empathic attitude and behavior; however, it is remained to cover the effective intensity of exercise on mammal empathy. Here, we tested the effects of light-intensity exercise, which has beneficial effects on expressing neurotrophic factors in the brain, on empathic behavior. Eight-week-old male C57BL/6 mice were subjected to forced wheel running at light-intensity (7.0 m/min, 30 min/day, 5 days/week) for 4 weeks. Then, all mice were subjected to helping behavior to evaluate their empathic behavior. The insular cortex was collected for analyzing the expressions of mRNA and miRNA. Four weeks of light-intensity exercise enhanced helping behavior. Exercised mice exhibited higher Bdnf gene expressions in the insular cortex than sedentary mice. In addition, there was a significant positive correlation between mRNA levels of Fndc5 and Bdnf in the insular cortex. Based on miRNA sequencing, 26 out of 51 miRNAs were significantly upregulated, and 25 out of 51 miRNAs were significantly downregulated in the insular cortex of mice with exercise. There were significant correlations between 11 out of 51 miRNAs and helping behavior; miR-486a-3p, which relates to FNDC5 expression, was contained. These results imply that miR-486a-3p/Fndc5/Bdnf pathway in the insular cortex would be a possible target for treating empathy.

Low-Carbohydrate and High-Protein Diet Suppresses Working Memory Function in Healthy Mice.

Low-carbohydrate and high-protein (LC-HP) diets are acceptable for improving physiological and metabolic parameters. However, the effects of LC-HP diets on the brain are unclear, which depend on glycometabolism for neuronal activity. Since astrocyte-neuron lactate shuttle (ANLS) is an essential pathway for maintaining brain functions, we investigated the changes in hippocampal memory function. In addition, the alteration of lactate transporter constituting ANLS and ANLS-related neurotrophic factors by feeding LC-HP diets was evaluated in healthy mice. C57BL/6 mice were divided into two groups: a group feeding LC-HP diet (24.6% carbohydrate, 57.6% protein, and 17.8% fat as percentages of calories) and a group feeding control diet (58.6% carbohydrate, 24.2% protein, and 17.2% fat as percentages of calories). Here, we found that 4 wk of LC-HP diet feeding suppressed memory function in mice evaluated by Y-maze. Hippocampal mRNA levels of lactate transporters, such as Mct1, Mct4, and Mct2, were unchanged with feeding LC-HP diets; however, LC-HP diets significantly decreased Dcx and Igf-1 receptor mRNA levels in the hippocampus. Bdnf and its related signaling in mice hippocampus exhibited no change by LC-HP diets. Although there was non-influence in the lactate-transport system, LC-HP diets would suppress hippocampal working memory with dysregulation of neuroplasticity. The current data propose the importance of food choices for maintaining hippocampal health.

A highly sensitive and selective UPLC-MS/MS assay for the determination of enarodustat (JTZ-951) in human plasma.

Enarodustat, a potent, orally bioavailable, selective inhibitor of hypoxia inducible factor-Prolyl hydroxylase (HIF-PH), has been approved recently in Japan for the treatment of anemia in patients with chronic kidney disease (CKD). To evaluate the pharmacokinetics of enarodustat, a bioanalytical assay in human plasma was needed for the quantitation of enarodustat for both healthy subjects and patients with CKD. The UPLC-MS/MS method for the quantitation of enarodustat was initially validated in a bioanalytical laboratory in Japan to support clinical studies conducted in Japan, and then was transferred and validated in a bioanalytical laboratory in United States to support clinical studies conducted here. A cross-validation was successfully performed between the two bioanalytical laboratories using both quality control (QC) samples and incurred study samples. Enarodustat was fortified with its isotopically labeled internal standard in a 25 µL plasma aliquot and extracted with protein precipitation. The chromatographic separation was achieved on an Acquity UPLC BEH C18 (1.7 µm, 2.1 × 50 mm) column with gradient elution. The calibration curve range for the assay was 1.00-500 ng/mL. Assay precision, accuracy, linearity, selectivity, sensitivity and analyte stability covering sample storage and analysis were established. No interferences were observed from medications that may be co-administered along with enarodustat. The validated UPLC-MS-MS method at the US bioanalytical laboratory has been successfully applied to eight clinical studies for the determination of enarodustat concentrations in human plasma for both healthy subjects and patients with CKD.

Characterization of gastrointestinal absorption of digoxin involving influx and efflux transporter in rats: application of mdr1a knockout (-/-) rats into absorption study of multiple transporter substrate.

1. This study was aimed to characterize gastrointestinal absorption of digoxin using wild-type (WT) and multidrug resistance protein 1a [mdr1a; P-glycoprotein (P-gp)] knockout (-/-) rats. 2. In WT rats, the area under the plasma concentration-time curve (AUC) of oral digoxin increased after oral pretreatment with quinidine at 30 mg/kg compared with non-treatment, but the increasing ratio tended to decrease at a high dose of 100 mg/kg. In mdr1a (-/-) rats, however, quinidine pretreatment caused a dose-dependent decrease in the AUC. 3. Quinidine pretreatment did not alter the hepatic availability of digoxin, indicating that the changes in the digoxin AUC were attributable to inhibition of the absorption process by quinidine; i.e. inhibition of influx by quinidine in mdr1a (-/-) rats and inhibition of efflux and influx by quinidine in WT rats. 4. An in situ rat intestinal closed loop study using naringin implied that organic anion transporting peptide (Oatp) 1a5 may be a responsible transporter in the absorption of digoxin. 5. These findings imply that the rat absorption behavior of digoxin is possibly governed by Oatp1a5-mediated influx and P-gp-mediated efflux. The mdr1a (-/-) rat is therefore a useful in vivo tool to investigate drug absorption associated with multiple transporters including P-gp.