Yoshiko Ogawa

Activation of CD11b+ Kupffer Cells/Macrophages as a Common Cause for Exacerbation of TNF/Fas-Ligand-Dependent Hepatitis in Hypercholesterolemic Mice

We have reported that the mouse hepatic injury induced by either α-galactosylceramide (α-GalCer) or bacterial DNA motifs (CpG-ODN) is mediated by the TNF/NKT cell/Fas-ligand (FasL) pathway. In addition, F4/80+ Kupffer cells can be subclassified into CD68+ subset with a phagocytosing capacity and CD11b+ subset with a TNF-producing capacity. CD11b+ subset increase if mice are fed high-fat and cholesterol diet (HFCD). The present study examined how a HFCD affects the function of NKT cells and F4/80+ CD11b+ subset and these hepatitis models. After the C57BL/6 mice received a HFCD, high-cholesterol diet (HCD), high-fat diet (HFD) and control diet (CD) for four weeks, the HFCD mice increased surface CD1d and intracellular TLR-9 expression by the CD11b+ population compared to CD mice. Hepatic injury induced either by α-GalCer or CpG-ODN was more severe in HCD and HFCD mice compared to CD mice, which was in proportion to the serum TNF levels. In addition, liver cholesterol levels but not serum cholesterol levels nor liver triglyceride levels were involved in the aggravation of hepatitis. The FasL expression of NKT cells induced by both reagents was upregulated in HFCD mice. Furthermore, the liver mononuclear cells and purified F4/80+ CD11b+ subset from HFCD mice stimulated with either reagent in vitro produced a larger amount of TNF than did those from CD mice. Intracellular TNF production in F4/80+ CD11b+ cells was confirmed. The increased number of F4/80+ CD11b+ Kupffer cells/macrophages by HFCD and their enhanced TNF production thus play a pivotal role in TNF/NKT cell/FasL dependent hepatic injury.

Physical Exercise with Multicomponent Cognitive Intervention for Older Adults with Alzheimer's Disease: A 6-Month Randomized Controlled Trial.

Aims: This study aimed to investigate the effect of 6-month physical exercise with a multicomponent cognitive program (MCP) on the cognitive function of older adults with moderate to severe Alzheimers disease (AD). Methods: We included 33 participants with AD in a 6-month randomized controlled trial. The intervention group participated in physical exercise and received a MCP. The control group received only the MCP. Before and after the intervention, cognitive outcomes were assessed using the Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Mini-Mental State Examination, and the Clock Drawing Test. Physical performance was evaluated by exercise time, the number of pedal rotation, total load, grip strength, and the Berg Balance Scale (BBS). Results: In all cognitive measures, there were no significant improvements between the two groups after 6 months in the baseline value-adjusted primary analysis. However, the ADAS-cog score was significantly lower between the two groups in secondary analysis adjusted for baseline value, age, sex, and education years. All physical outcomes were significantly higher in the intervention group except for total load compared with baseline measurements. Conclusion: This study indicates that it is possible to improve cognitive function in older adults with moderate to severe AD through 6-month physical exercise with a multicomponent cognitive intervention.

Chronic Running Exercise Alleviates Early Progression of Nephropathy with Upregulation of Nitric Oxide Synthases and Suppression of Glycation in Zucker Diabetic Rats

Exercise training is known to exert multiple beneficial effects including renal protection in type 2 diabetes mellitus and obesity. However, the mechanisms regulating these actions remain unclear. The present study evaluated the effects of chronic running exercise on the early stage of diabetic nephropathy, focusing on nitric oxide synthase (NOS), oxidative stress and glycation in the kidneys of Zucker diabetic fatty (ZDF) rats. Male ZDF rats (6 weeks old) underwent forced treadmill exercise for 8 weeks (Ex-ZDF). Sedentary ZDF (Sed-ZDF) and Zucker lean (Sed-ZL) rats served as controls. Exercise attenuated hyperglycemia (plasma glucose; 242 ± 43 mg/dL in Sed-ZDF and 115 ± 5 mg/dL in Ex-ZDF) with increased insulin secretion (plasma insulin; 2.3 ± 0.7 and 5.3 ± 0.9 ng/mL), reduced albumin excretion (urine albumin; 492 ± 70 and 176 ± 11 mg/g creatinine) and normalized creatinine clearance (9.7 ± 1.4 and 4.5 ± 0.8 mL/min per body weight) in ZDF rats. Endothelial (e) and neuronal (n) NOS expression in kidneys of Sed-ZDF rats were lower compared with Sed-ZL rats (p<0.01), while both eNOS and nNOS expression were upregulated by exercise (p<0.01). Furthermore, exercise decreased NADPH oxidase activity, p47phox expression (p<0.01) and α-oxoaldehydes (the precursors for advanced glycation end products) (p<0.01) in the kidneys of ZDF rats. Additionally, morphometric evidence indicated renal damage was reduced in response to exercise. These data suggest that upregulation of NOS expression, suppression of NADPH oxidase and α-oxoaldehydes in the kidneys may, at least in part, contribute to the renal protective effects of exercise in the early progression of diabetic nephropathy in ZDF rats. Moreover, this study supports the theory that chronic aerobic exercise could be recommended as an effective non-pharmacological therapy for renoprotection in the early stages of type 2 diabetes mellitus and obesity.

Music Attenuated a Decrease in Parasympathetic Nervous System Activity after Exercise

Music and exercise can both affect autonomic nervous system activity. However, the effects of the combination of music and exercise on autonomic activity are poorly understood. Additionally, it remains unknown whether music affects post-exercise orthostatic tolerance. The aim of this study was to evaluate the effects of music on autonomic nervous system activity in orthostatic tolerance after exercise. Twenty-six healthy graduate students participated in four sessions in a random order on four separate days: a sedentary session, a music session, a bicycling session, and a bicycling with music session. Participants were asked to listen to their favorite music and to exercise on a cycle ergometer. We evaluated autonomic nervous system activity before and after each session using frequency analysis of heart rate variability. High frequency power, an index of parasympathetic nervous system activity, was significantly increased in the music session. Heart rate was increased, and high frequency power was decreased, in the bicycling session. There was no significant difference in high frequency power before and after the bicycling with music session, although heart rate was significantly increased. Additionally, both music and exercise did not significantly affect heart rate, systolic blood pressure or also heart rate variability indices in the orthostatic test. These data suggest that music increased parasympathetic activity and attenuated the exercise-induced decrease in parasympathetic activity without altering the orthostatic tolerance after exercise. Therefore, music may be an effective approach for improving post-exercise parasympathetic reactivation, resulting in a faster recovery and a reduction in cardiac stress after exercise.

Cognitive Dysfunction and Malnutrition Are Independent Predictor of Dysphagia in Patients with Acute Exacerbation of Congestive Heart Failure.

Early detection and intervention for dysphagia is important in patients with congestive heart failure (CHF). However, previous studies have focused on how many patients with dysphagia develop CHF. Studies focusing on the comorbidity of dysphagia in patients with CHF are rare. Additionally, risk factors for dysphagia in patients with CHF are unclear. Thus, the aim of this study was to clarify risk factors for dysphagia in patients with acute exacerbation of CHF. A total of 105 patients, who were admitted with acute exacerbation of CHF, were enrolled. Clinical interviews, blood chemistry analysis, electrocardiography, echocardiography, Mini-Mental State Examination (MMSE), exercise tolerance tests, phonatory function tests, and evaluation of activities of daily living (ADL) and nutrition were conducted on admission. After attending physicians permitted the drinking of water, swallowing screening tests were performed. Patients were divided into a dysphagia group (DG) or a non-dysphagia group (non-DG) based on Functional Oral Intake Scale level. Among the 105 patients, 38 had dysphagia. A greater number of patients had history of aspiration pneumonia and dementia, and there was a higher age, N-terminal pro-B-type natriuretic peptide level in the DG compared with the non-DG. MMSE scores, exercise tolerance, phonatory function, status of ADL, nutrition, albumin, and transthyretin were lower in the DG compared with the non-DG. In multivariate analysis, after adjusting for age and sex, MMSE, BI score, and transthyretin was independently associated with dysphagia. Comorbidity of dysphagia was 36.1% in patients with acute exacerbation of CHF, and cognitive dysfunction and malnutrition may be an independent predictor of dysphagia.

Arterial Stiffness Measured with the Cuff Oscillometric Method Is Predictive of Exercise Capacity in Patients with Cardiac Diseases.

Arterial stiffness is widely used in assessing arteriosclerosis in the background of increased cardiovascular events. Arteriosclerosis also causes reduction in exercise capacity, which is a most important prognostic factor in patients with cardiovascular disease; however, data on the association between arterial stiffness and exercise capacity are limited. Therefore, a simple and noninvasive measurement of arterial stiffness that reflects the central circulation and exercise capacity is needed. The arterial velocity pulse index (AVI) is a parameter of arterial stiffness measurable with the cuff oscillometric method; however, the clinical utility of this method is unclear. We aimed to evaluate the trend of AVI in patients with coronary artery disease (CAD), and the association between AVI and exercise capacity. A cross-sectional study of 116 patients with cardiac disease (34 CAD and 82 non-CAD patients) was performed. Non-CAD patients were those with any cardiac diseases who did not have proven CAD. The results showed that the AVI was significantly higher in CAD patients than non-CAD patients (P < 0.05, analysis of covariance). The AVI was inversely correlated with peakVO2 (r = -0.239, P < 0.05) and was a significant explanatory variable for peakVO2 in stepwise regression analysis (β = -14.62, t = -2.5, P < 0.05). These results indicate that the AVI is strongly associated with CAD and predictive of the exercise capacity in patients with cardiac diseases. We, therefore, propose that the cuff oscillometric method is clinically useful in evaluating arterial stiffness in patients with cardiac diseases, especially CAD.

The Effect of Synthetic C-Reactive Protein on the In Vitro Immune Response of Human PBMCs Stimulated with Bacterial Reagents

Synthetic C-reactive protein (CRP) rescues mice from lethal endotoxin shock or bacterial infection by suppressing tumor necrosis factor (TNF-α), but in turn, enhances Kupffer cell phagocytic activity. We herein assessed the influence of CRP in human peripheral blood mononuclear cells (PBMCs). When human PBMCs were stimulated in vitro with penicillin-treated Streptococcus pyogenes, bacterial DNA motifs and lipopolysaccharide with or without synthetic CRP, CRP suppressed the production of TNF-α and IL-12, but not that of IFN-γ. This was also the case for the in vitro Shwartzman reaction induced in PBMCs. CRP also decreased high-mobility group box 1 production from macrophages, which is crucial in the later phase of endotoxin/septic shock. However, CRP upregulated the perforin expression by CD56+ NK cells and increased their antitumor cytotoxicity. CRP may thus be a potent immunomodulatory factor in the human immune system, suggesting its therapeutic potential for use against human septic shock.

Angiotensin II upregulates CYP4A isoform expression in the rat kidney through angiotensin II type 1 receptor

Angiotensin II (AngII) stimulates the renal production and release of 20-hydroxyeicosatetraenoic acids (20-HETE), which is a major metabolite of arachidonic acid catalyzed by CYP4A isoforms. However, the effects of AngII on CYP4A isoform expression in the kidney and its mechanism remains unclear. To clarify the regulation of CYP4A isoform expression by AngII, we examined the chronic effects of AngII and AngII type 1 receptor (AT1-R) blockade on CYP4A isoform expression. Sprague-Dawley rats were infused with vehicle or AngII for 1 week, and the AngII-infused rats were also treated with or without the AT1-R blocker, candesartan. AngII increased CYP4A isoform protein expression in the renal cortex (CO) and outer medulla (OM) in a dose-dependent manner, and candesartan inhibited the AngII-increased CYP4A expression in a dose-dependent manner. AngII increased the CYP4A isoform mRNA expression in the CO and OM, and candesartan inhibited AngII-increased CYP4A isoform mRNA expression. These results indicated that AngII chronically increased the CYP4A isoform expression in the rat kidney. The AngII-induced CYP4A isoform expression was mediated by AT1-R.

Pitavastatin Upregulates Nitric Oxide Synthases in the Kidney of Spontaneously Hypertensive Rats and Wistar–Kyoto Rats

BACKGROUND Clinical trials show potent renoprotective effects of pitavastatin (PTV), although the precise mechanism for these renoprotective effects is not fully clarified. The aim of this study was to examine the antihypertensive and renoprotective effects of PTV, focusing on the nitric oxide (NO) system. METHODS Male, 6-week-old, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were randomized to receive vehicle or PTV (2 mg/kg bodyweight) for 8 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks. After 8 weeks, plasma biochemical parameters and renal histology were examined. NO synthase isoform (neuronal, nNOS; inducible, iNOS; and endothelial, eNOS) expression and eNOS phosphorylation were examined by western blotting. RESULTS PTV attenuated hypertension and albuminuria development in SHR. PTV decreased glomerular desmin expression and medullary interstitial fibrosis in SHR. PTV tended to increase plasma NO in both strains but significantly increased urinary NO excretion only in WKY. PTV significantly increased nNOS and eNOS expression, enhanced eNOS phosphorylation at serine1177, and inhibited eNOS phosphorylation at threonine495 in the kidney of both strains. CONCLUSIONS PTV treatment led to increased renal NOS expression and upregulated eNOS activity in both SHR and WKY. The antihypertensive and renoprotective effects of PTV may be related to upregulation of the NO system.

Six-Month Lower Limb Aerobic Exercise Improves Physical Function in Young-Old, Old-Old, and Oldest-Old Adults

The effect of aerobic exercise on physical function and mental health in various adult age groups (young-old, 65-74; old-old, 75-84; oldest-old, ≥ 85 years) is unclear. The aim of this study was to investigate the effects of the Kohzuki Exercise Program (KEP) on physical function and mental health in these age groups. The KEP consisted of 40-min supervised sessions 3 times per week for 6 months as follows: 5 min of warm-up, 30 min of lower limb aerobic exercise, and 5 min of cool-down. A total of 50 participants (22 young-old, 20 old-old, and 8 oldest-old) who participated in the KEP completed at least 88% of the sessions. In statistical analysis, 3 (group: oldest-old, old-old, young-old) × 2 (time: baseline and after 6 months) analyses of variance were used to determine if there were significant main and interaction effects. Significant interactions were probed using the post-hoc paired t test. The Short Physical Performance Battery (SPPB) score showed significant group × time interactions after 6 months (p = 0.031). In the post-hoc test, oldest-old (p < 0.001), old-old (p < 0.001), and young-old (p < 0.01) groups had significantly better physical function after 6 months. However, none of the mental health measures showed group × time interactions at 6-month. Our results suggest that a 6-month KEP led to improved physical function in oldest-old, old-old, and young-old adults. The KEP was effective for oldest-old adults in particular. The KEP exhibits good adherence, making it suitable for a wide age range in society.