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.

The Influences of Changes in Physical Activity Levels With Easing Restriction of Access to the University Campus on Empathy and Social Supports in College Students During the COVID-19 Pandemic.

College students in Japan are restricted from accessing the campus associated with promoting online classes during the COVID-19 pandemic; it would lead to less physical activity and poor relationships with others. Here, we measured 887 college students' amounts of physical activity, sitting time, self-reported cognitive and affective empathy, and perceived social support before and after easing campus entrance restrictions. The amounts of total activity, vigorous-intensity, and moderate-intensity activity in college students, both male and female, increased after easing restrictions of accessing the campus compared during restrictions. The amounts of walking activity were unchanged. Self-reported cognitive empathy scores significantly increased in female students after mitigating restrictions, but not in males. Furthermore, the total of physical activity's change amounts was positively correlated with changes in the scores of affective empathy and perceived family support. In addition, changes in the scores of affective empathy were positively correlated with perceived social help from family, friends, and close people. The current findings imply that increasing physical activity levels after easing restriction of access to the campus would lead to a better quality of life in young adults during the COVID-19 pandemic.

Long-term light and moderate exercise intervention similarly prevent both hippocampal and glycemic dysfunction in presymptomatic type 2 diabetic rats.

A prediabetic population has an increased risk of cognitive decline and type 2 diabetes mellitus (T2DM). This study investigated whether the progression of memory dysfunction and dysregulated brain glycogen metabolism is prevented with 4 mo of exercise intervention from the presymptomatic stage in a T2DM rat model. Memory function and biochemical and molecular profiles were assessed in the presymptomatic stage of Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, a T2DM model, with Long-Evans Tokushima (LETO) rats as genetic control. These rats were subjected to light- or moderate-intensity treadmill running for 4 mo with repetition of the same experiments. Significant hippocampal-dependent memory dysfunction was observed in the presymptomatic stage of OLETF rats, accompanied by downregulated levels of hippocampal monocarboxylate transporter 2 (MCT2), a neuronal lactate-transporter, without alteration in hippocampal glycogen levels. Four months of light or moderate exercise from the presymptomatic stage of T2DM normalized glycemic parameters and hippocampal molecular normalization through MCT2, glycogen, and brain-derived neurotrophic factor (BDNF) levels with the improvement of memory dysfunction in OLETF rats. A 4-mo exercise regimen from the presymptomatic stage of T2DM at a light and moderate intensities contributed to the prevention of the development of T2DM and the progression of cognitive decline with hippocampal lactate-transport and BDNF improvement.NEW & NOTEWORTHY Type 2 diabetes mellitus is an independent risk factor for hippocampal memory dysfunction, which would progress since the prediabetic stage. We found that 4 mo of exercise both at the light and moderate intensity prevented the progression of memory dysfunction with an improvement of hippocampal MCT2 expression in presymptomatic diabetes, implying that light intensity exercise could be a therapeutic approach, and the alteration of hippocampal MCT2 would be a therapeutic target of memory dysfunction from presymptomatic diabetes.

Exercise-Induced Adrenocorticotropic Hormone Response Is Cooperatively Regulated by Hypothalamic Arginine Vasopressin and Corticotrophin-Releasing Hormone.

INTRODUCTION: Exercise becomes a stress when performed at an intensity above the lactate threshold (LT) because at that point the plasma adrenocorticotropic hormone (ACTH), a marker of stress response, increases. It is possible that the exercise-induced ACTH response is regulated at least by arginine vasopressin (AVP) and possibly by corticotropin-releasing hormone (CRH), but this remains unclear. To clarify the involvement of these factors, it is useful to intervene pharmacologically in the regulatory mechanisms, with a physiologically acceptable exercise model. METHODS: We used a special stress model of treadmill running (aerobic exercise) for male Wistar rats, which mimic the human physiological response, where plasma ACTH levels increase at just above the LT for 30 min. Animals were administered the AVP V1b receptor antagonist SSR149415 (SSR) and/or the CRH type 1 receptor antagonist CP154526 (CP) intraperitoneally before the exercise, which allowed the monitoring of exercise-induced ACTH response. Immunohistochemical evaluation of activated AVP and CRH neurons with exercise was performed for the animals' hypothalami. RESULTS: A single injection of either antagonist, SSR or CP, resulted in inhibited ACTH levels after exercise stress. Moreover, the combined injection of SSR and CP strongly suppressed ACTH secretion during treadmill running to a greater extent than each alone. The running-exercise-induced activation of both AVP and CRH neurons in the hypothalamus was also confirmed. CONCLUSION: These results lead us to hypothesize that AVP and CRH are cooperatively involved in exercise-induced ACTH response just above the LT. This may also reflect the stress response with moderate-intensity exercise in humans.

Mental Health Status and Related Factors Among Visually Impaired Athletes.

BACKGROUND: A growing body of pieces of evidence suggests that sport activity is of potential importance both for physical and mental health. To date, there is a lack of information and evidence regarding the mental health of visually impaired people playing some extent of sports and recognized as athletes with renowned career track. The present study aims to clarify the mental health status and its related factors in visually impaired athletes. METHODS: The current study was a questionnaire-based cross-sectional investigation. Visually impaired athletes (n = 81; men: 72.8%; average age: 32.8 ± 12.0 years) engaged in Paralympic sports events namely track and field (marathon), goalball, swimming, blind soccer, and judo were the study subjects from leading institutions in Japan. A diverse range of issues were included in a questionnaire survey like attributes, condition of visual impairment, competition activities, competition stressors, social support, and mental health status (recorded through the K6 scale). Logistic regression analyses were performed with mental health status as a dependent variable and other studied parameters as independent variables. RESULTS: A total of 21.0% of study participants (11.9% of men and 45.5% of women) showed bad mental health condition. Results of multivariate logistic regression analysis showed that "female" (odds ratio (OR) 11.94, 95% confidence interval (CI) 2.60 - 54.76, P = 0.001), "higher evaluation from one's surroundings for competition stressors" (OR 5.74, 95% CI 1.34 - 24.60, P = 0.019), and "lower social support from family members" (OR 3.97, 95% CI 1.03 - 15.25, P = 0.045) were the risk factors of bad mental health. CONCLUSIONS: The mental health status among visually impaired athletes might be almost the same level as non-visually impaired athletes and general population, and have relation to gender, stress of evaluation from surroundings during competition, and social support from family members. It may be necessary to pay attention especially to women, and improve one's surroundings of competition stressors and family social support to maintaining the mental health of visually impaired athletes.

Variation of Salivary IgA During Weight Loss Period Before a Competition Among University Judo Players.

BACKGROUND: This study aims to investigate the health condition of university judo athletes during a period of weight loss before a competition, using secretory immunoglobulin A (SIgA) in saliva. METHODS: The subjects were 30 university judo athletes, who were divided into three groups: control group (n = 10), under 5% weight loss group (n = 10), and over 5% weight loss group (n = 10). The items evaluated were body weight measurements, salivary SIgA level and its secretion rates, incidences of symptoms of upper respiratory tract infections, and mental state. RESULTS: The over 5% body weight loss group had significantly lower SIgA secretion rates on the first day and third day before the real competition compared to those of the control group. Furthermore, the over 5% body weight loss group had an increased number of symptoms of upper respiratory tract infections. Alterations in mental statuses were also seen, such as decreased vitality and increased fatigue on the day before the competition in the over 5% weight loss group. CONCLUSIONS: This study shows that over 5% body weight loss in judo athletes induces a decrease in the salivary SIgA secretion rate and causes health condition of the body and the mind to deteriorate.

Dysregulation of Glycogen Metabolism with Concomitant Spatial Memory Dysfunction in Type 2 Diabetes: Potential Beneficial Effects of Chronic Exercise.

Cognitive dysfunction is one of the comorbidities of diabetes mellitus, but hippocampus-dependent learning and memory, a component of cognitive function, shows particular decline in type 2 diabetes, suggesting an increased risk for dementia and Alzheimer's disease. Cognitive function is related to dysregulated glucose metabolism, which is the typical cause of type 2 diabetes; however, hippocampal glycogen and its metabolite lactate are also crucial for hippocampus-dependent memory function. Type 2 diabetes induced hippocampus-dependent learning and memory dysfunction can be improved by chronic exercise and this improvement may possibly mediate through an adaptation of the astrocyte-neuron lactate shuttle (ANLS). This chapter focuses on the dysregulation of hippocampal glycometabolism in type 2 diabetes examining both existing evidence as well as the potential underlying pathophysiological mechanism responsible for memory dysfunction in type 2 diabetes, and showing for the first time that chronic exercise could be an effective therapy for type-2-diabetes-induced hippocampal memory decline.

Effects of Repetitive Altitude Training on Salivary Immunoglobulin A Secretion in Collegiate Swimmers.

BACKGROUND: Altitude training has often been conducted just before main competition games in many sports. An increase in the frequency of upper respiratory tract infections and gastrointestinal infections due to an altitude-induced suppression of the immune system has been reported after altitude training. Salivary secretory immunoglobulin A (SIgA) is the major immunoglobulin of the mucosal immune system. A suppressive effect of heavy training on SIgA has been reported. However, little is known regarding the effects of repetitive altitude training and hypoxic exposure on SIgA. The objective of this study was to evaluate the changes in SIgA in swimmers undergoing repetitive altitude training at 1,900 m. METHODS: Nine collegiate swimmers who experienced their first altitude training experience (FT group) were compared to nine swimmers who experienced repetitive training (RT group) and non-training subjects (Con group). Saliva was collected before ascent and eight times every 2 days during altitude training. SIgA levels were measured by enzyme-linked immunosorbent assays. RESULTS: Compared to the Con group, SIgA levels and the secretion velocity were decreased after ascent and were slowly restored in both the FT and RT groups. The chronological trends in SIgA levels were similar, even though the decline in SIgA levels in the FT group was larger than that in the RT group. CONCLUSION: Altitude training and experience with altitude training may be one of the factors influencing SIgA.

Assessment of Salivary Nitric Oxide Levels in Elite University Athletes in Japan: Findings From a Cross Sectional Study Design.

BACKGROUND: High-intensity exercise affects the level of salivary nitric oxide (NO) with an impact on oxidative stress such as a reactive nitrogen-oxide species. However, in athletes with high-intensity training, the relationship between salivary NO levels and oxidative stress is yet to be clear. Additionally, the association of salivary NO levels and the common health disorders of athletes is unknown. Thus, the aim of this cross-sectional study was to clarify the relationship between salivary NO levels and oxidative stress, and the health/medical disorders existing in elite class university athletes. METHODS: In 250 athletes (males, 151 and females, 99) from undergraduate levels of Japanese University, we investigated the relationship between levels of salivary NO and oxidative stress markers: derived reactive oxygen species (d-ROMs) and biological antioxidant potential (BAP), and also examined that whether salivary NO levels are associated with diseases. RESULTS: There were no significant association between the levels of salivary NO and oxidative stress markers (such as d-ROM and BAP). From the questionnaire, asthma was the most prevalent as evident from medical history of the athletes. Additionally, the salivary NO levels were higher (520 ± 43 µmol/L vs. 375 ± 13 µmol/L, P < 0.05) in the asthma group (n = 9) than in the non-asthma group (n = 241). We determined the optimal cut-off value (P = 0.019) of the salivary NO levels for asthma was 425 µmol/L, with a sensitivity of 88.9% and specificity of 61.8% (area under the curve (AUC), 0.73). CONCLUSIONS: Our results suggest that the high levels of salivary NO in trained university athletes in Japan may potentially predict asthma. And this salivary NO level is not associated with markers of oxidative stress and existing diseases in athletes studied here.

Development of the Japanese version of the Preschool Confusion Assessment Method for the ICU.

Aim: Delirium is associated with various negative clinical outcomes, such as decline in cognitive ability, increased length of hospital stay, and higher mortality. For these reasons, early diagnosis of delirium is critical. Unfortunately, there are no reliable diagnostic criteria or tool of delirium for infants and preschool-aged children in Japan.The aim of the present study was to translate a new delirium assessment tool, the Preschool Confusion Assessment Method for the Intensive Care Unit (psCAM-ICU), for accurately diagnosing clinically ill infants and preschool-aged children, from English to Japanese. Methods: The translation was undertaken with the internationally established back-translation method. The translation was repeated blindly and independently by eight medical researchers and clinicians from multiple disciplines. Any discrepancy evident from the translated works was discussed and resolved. Results: We report the successful development of the Japanese version of psCAM-ICU. However, before its full application, this diagnostic tool requires further testing and study, most notably for its validation and reliability. Conclusion: A Japanese version of the psCAM-ICU was developed.

Hyper-hippocampal glycogen induced by glycogen loading with exhaustive exercise.

Glycogen loading (GL), a well-known type of sports conditioning, in combination with exercise and a high carbohydrate diet (HCD) for 1 week enhances individual endurance capacity through muscle glycogen supercompensation. This exercise-diet combination is necessary for successful GL. Glycogen in the brain contributes to hippocampus-related memory functions and endurance capacity. Although the effect of HCD on the brain remains unknown, brain supercompensation occurs following exhaustive exercise (EE), a component of GL. We thus employed a rat model of GL and examined whether GL increases glycogen levels in the brain as well as in muscle, and found that GL increased glycogen levels in the hippocampus and hypothalamus, as well as in muscle. We further explored the essential components of GL (exercise and/or diet conditions) to establish a minimal model of GL focusing on the brain. Exercise, rather than a HCD, was found to be crucial for GL-induced hyper-glycogen in muscle, the hippocampus and the hypothalamus. Moreover, EE was essential for hyper-glycogen only in the hippocampus even without HCD. Here we propose the EE component of GL without HCD as a condition that enhances brain glycogen stores especially in the hippocampus, implicating a physiological strategy to enhance hippocampal functions.

Differential effects of type 2 diabetes on brain glycometabolism in rats: focus on glycogen and monocarboxylate transporter 2.

Astrocyte-neuron lactate shuttle (ANLS) is a pathway that supplies glycogen-derived lactate to active neurons via monocarboxylate transporter 2 (MCT2), and is important for maintaining brain functions. Our study revealed alterations of ANLS with hippocampal hyper-glycogen levels and downregulated MCT2 protein levels underlying hippocampal dysfunctions as a complication in type 2 diabetic (T2DM) animals. Since T2DM rats exhibit brain dysfunctions involving several brain regions, we examined whether there might also be T2DM effects on ANLS's disturbances in other brain loci. OLETF rats exhibited significantly higher glycogen levels in the hippocampus, hypothalamus, and cerebral cortex than did LETO rats. MCT2 protein levels in OLETF rats decreased significantly in the hippocampus and hypothalamus compared to their controls, but a significant correlation with glycogen levels was only observed in the hippocampus. This suggests that the hippocampus may be more vulnerable to T2DM compared to other brain regions in the context of ANLS disruption.

Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is likely to be an independent risk factor for hippocampal-based memory dysfunction, although this complication has yet to be investigated in detail. As dysregulated glycometabolism in peripheral tissues is a key symptom of type 2 diabetes, it is hypothesised that diabetes-mediated memory dysfunction is also caused by hippocampal glycometabolic dysfunction. If so, such dysfunction should also be ameliorated with moderate exercise by normalising hippocampal glycometabolism, since 4 weeks of moderate exercise enhances memory function and local hippocampal glycogen levels in normal animals. METHODS: The hippocampal glycometabolism in OLETF rats (model of human type 2 diabetes) was assessed and, subsequently, the effects of exercise on memory function and hippocampal glycometabolism were investigated. RESULTS: OLETF rats, which have memory dysfunction, exhibited higher levels of glycogen in the hippocampus than did control rats, and breakdown of hippocampal glycogen with a single bout of exercise remained unimpaired. However, OLETF rats expressed lower levels of hippocampal monocarboxylate transporter 2 (MCT2, a transporter for lactate to neurons). Four weeks of moderate exercise improved spatial memory accompanied by further increase in hippocampal glycogen levels and restoration of MCT2 expression independent of neurotrophic factor and clinical symptoms in OLETF rats. CONCLUSIONS/INTERPRETATION: Our findings are the first to describe detailed profiles of glycometabolism in the type 2 diabetic hippocampus and to show that 4 weeks of moderate exercise improves memory dysfunction in type 2 diabetes via amelioration of dysregulated hippocampal glycometabolism. Dysregulated hippocampal lactate-transport-related glycometabolism is a possible aetiology of type-2-diabetes-mediated memory dysfunction.

Landiolol hydrochloride ameliorates acute lung injury in a rat model of early sepsis through the suppression of elevated levels of pulmonary endothelin-1.

Among the dysfunctions and pathologies associated with sepsis, the underlying molecular mechanisms of sepsis-induced acute lung injury (ALI) are poorly understood. Endothelin (ET)-1, a potent vasoconstrictor and pro-inflammatory peptide, is known to be involved in the pathogenesis of ALI in a rat model of sepsis. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting ß-blocker, plays a crucial role in ameliorating and attenuating LPS-induced ALI through modulation of the ET-1 system. Male Wistar rats at 8weeks of age were administered with either saline or lipopolysaccharide (LPS) for three hours (3h) and some of the LPS-administered rats were continuously treated with landiolol for 3h. ALI was induced by LPS, including levels of both circulatory and pulmonary TNF-α and IL-6 but [PaO2] was significantly decreased. LPS also induced a significant increase in levels of pulmonary ET-1 and ET-A receptor, but levels of ET-B receptor, which has vasodilating effects, were remarkably diminished. Further, LPS administration upregulated the pulmonary expression of HIF-1α. Finally, the treatment of LPS-administered rats with landiolol for 3h ameliorated and prevented ALI, normalized the altered levels of pulmonary ET-1 and ET-A receptors. Landiolol also induced significant down-regulation of ET-B receptor in lung tissues in the early hours (phase) of sepsis. However, Landiolol treatment had no effect on the up-regulated inflammatory mediators (TNF-α, IL-6) in both plasma and lung tissues during sepsis, and expression of pulmonary HIF-1α also remained unchanged after landiolol treatment. Collectively, these data led us to conclude that landiolol may ameliorate sepsis-induced ALI via the pulmonary ET system.

Activated protein C does not increase in the early phase of trauma with disseminated intravascular coagulation: comparison with acute coagulopathy of trauma-shock.

We hypothesized that activated protein C does not increase in disseminated intravascular coagulation (DIC) after trauma and that the same is true for acute coagulopathy of trauma-shock (ACOTS). Activated protein C levels were prospectively measured in 57 trauma patients: 30 with DIC and 27 without DIC. Normal to more decreased activated protein C levels were observed in DIC patients than in the controls and non-DIC patients. The activated protein C levels in ACOTS patients were similar to those in DIC patients. In conclusion, activated protein C does not increase in either DIC or ACOTS in the early phase of trauma.