Kasumi Mikami

Nutritional regulation of coupling factor 6, a novel vasoactive and proatherogenic peptide

High sodium, high glucose, and obesity are important risk factors for age-related diseases such as cardiovascular disease (CVDs), stroke, and cancer. Coupling factor 6 (CF6) is released from vascular endothelial cells and functions as a circulating peptide that inhibits prostacyclin and nitric oxide generation by intracellular acidosis. High glucose elevates CF6 by activation of protein kinase C and p38 mitogen-activated protein kinase, whereas CF6 causes type 2 diabetes mellitus, resulting in a high glucose vicious cycle. Low glucose increases inhibitory factor peptide 1, an endogenous inhibitor of CF6. High salt intake increases CF6 through nuclear factor κB signaling, whereas CF6 induces salt-sensitive hypertension and salt-induced congestive heart failure. Oral administration of vitamin C cancels salt-induced increase in CF6, and estrogen replacement leads to the delayed onset of CF6-induced salt-sensitive hypertension and the rescue from cardiac systolic dysfunction. Because CF6 contributes to the onset of CVDs, nutritional regulation of CF6 will shed light on the understanding of preventive strategy and mechanisms for CVDs and a target for therapy.

Educational Method for Developing Assessment Skills of Nursing Students

This study aimed to verify the effects of a new instructional method to structure knowledge. The research hypothesis was that “Structured knowledge improves assessment skills of students”. Fifty-five second-year undergraduate students volunteered to participate in this study. They were randomized into either a group that received instructional intervention (n = 19; intervention) or a group that did not (n = 36; non-intervention). A survey and instructional intervention comprised pre-tests, individual instructional intervention, participant self-studies and post-tests. The students attempted one pre- and one post-test task, each comprising concept map drawing and assessment of actual patients with diabetes. Participants who received educational intervention described concept maps regarding the pathophysiology and nursing of diseases, and we taught a learning strategy to understand relationships between concepts and the assumption of clinical assessment. The results of the concept map drawing task showed that post-test structural knowledge scores were significantly higher for the intervention, than the non-intervention group (p < 0.001). Post-test scores of the intervention group for assessment skills regarding “nursing problems and factors” were significantly better than pre-test scores (p < 0.001), and significantly higher than those for the non-intervention group (p < 0.01). The educational intervention in this study seemed to augment the ability to identify nursing problems, although we did not teach assessment strategies. The intervention seemed to confer structured knowledge with explicit conditions for applicability. Structured knowledge with explicit conditions and learning how to use knowledge to assess patients before a clinical practicum seemed to augment assessment skills.

Spontaneous Micro-Aggregation of Platelets Predicts Clinical Outcome in Acute Ischemic Stroke

BACKGROUNDS Spontaneous micro-aggregation of platelets (SMAP) is frequently observed in stroke patients and is a trigger for the additional development of larger thrombi. We tested the hypothesis that SMAP may predict clinical outcome in acute ischemic stroke patients. METHODS AND RESULTS Consecutive acute ischemic stroke patients (n = 358) who were transferred to our hospital within 24 hours after its onset were enrolled. Peripheral venous blood was sampled to measure various parameters when they arrived. SMAP was correlated with plasma brain natriuretic peptide and diastolic blood pressure positively, and with serum albumin and body weight negatively. Multivariable Cox regression analysis showed that only serum albumin was an independent predictor of the SMAP (P = .0023). The proportion of patients who were functionally independent (score 0-2 on the modified Rankin Scales) at discharge was lower in the third tertile of SMAP (higher level) as compared with the first and the second tertiles in ischemic stroke (odds ratio [OR], 5.76; 95 % confidence interval [CI], 3.31-10.05; P < .0001) and atherothrombotic stroke (P = .02 by chi-square test). The lower proportion of patients achieving independence was found in the first tertile of serum albumin (lower level) as compared with the second and third tertiles in ischemic (OR, 4.60; 95% CI, 2.66-7.95; P < .0001), atherothrombotic, and cardioembolic stroke (P = .004 and P < .0001 by chi-square test). On logistic regression analysis, SMAP and serum albumin remained independent predictors of poor outcome in ischemic stroke. CONCLUSIONS SMAP within 24 hours after stroke onset is a novel independent predictor of clinical outcome in acute ischemic stroke patients.

Intracellular protons accelerate aging and switch on aging hallmarks in mice: OSANAI et al.

Diet‐induced metabolic acidosis is associated with the impairment of bone metabolism and an increased risk of a number of chronic noncommunicable diseases, such as type 2 diabetes mellitus and hypertension. The serum bicarbonate level is an independent predictor of chronic kidney disease progression. We investigated whether proton accelerates aging by analyzing both coupling factor 6‐overexpressing transgenic (TG) and high salt‐fed mice which display sustained intracellular acidosis, due to enhanced proton import through ecto‐F1Fo complex and/or reduced proton export through Na+‐K+ ATPase inhibition. Both types of mice displayed shortened lifespan and early senescence‐associated phenotypes such as signs of hair greying and alopecia, weight loss, and/or reduced organ mass. In chronic intracellular acidosis mice, autophagy was impaired by regression of Atg7, an increase in nuclear acetylated LC3 II, and acetylation of Atg7. The increase in histone 3 trimethylation at lysine 4 (H3K4me3) and H4K20me3 and the decrease in H3K9me3 and H3K27me3 were observed in the heart and kidney obtained from both TG and high salt‐fed mice. The decrease in lamin A/C, emerin, and heterochromatin protein 1α without changes in barrier‐to‐autointegration factor and high‐mobility group box 1 was confirmed in TG and high salt‐fed mice. Suppression of nuclear histone deacetylase 3‐emerin system is attributable to epigenetic regression of Atg7 and H4K5 acetylation. These findings will shed light on novel aging and impaired autophagy mechanism, and provide implications in a target for antiaging therapy.

Mitochondrial inhibitory factor protein 1 attenuates coupling factor 6-induced aging signal

Coupling factor 6 (CF6) forces a counter‐clockwise rotation of plasma membrane F1Fo complex, resulting in proton import and accelerated aging. Inhibitory factor peptide 1 (IF1) suppresses a unidirectional counter‐clockwise rotation of F1Fo complex without affecting ATP synthesis. We tested the hypothesis that IF1 may attenuate CF6‐induced aging signaling in CF6‐overexpressing transgenic (TG) cells. In IF1‐GFP overexpressing wild type (WT) cells, the diffuse peripheral staining of tubular mitochondria was observed with a dense widely distributed network around the nucleus. In TG cells, however, the only peri‐nuclear network of fragmented mitochondria was observed at 24 h, but it was developed to a widely distributed mitochondrial network of tubular mitochondria at 72 h. TG cells displayed aging hallmarks of telomere attrition, epigenetic alterations, defective proteostasis, and genomic instability with a decrease in emerin and lamin and loss of heterochromatin. IF1 induction rescued TG cells from telomere attrition, expression of genomic instability with the increase in emerin and lamin, and that of epigenetic alterations with recovery of heterochromatin. In defective proteostasis, IF1 induction restored a potent peri‐nuclear staining of autolysosomes compared with the baseline weak staining. The decrease in Atg7 was restored, whereas the increase in P62 was abolished. We conclude that genetic disruption of proton signals by IF1 induction suppressed CF6‐induced expression of aging hallmarks such as telomere attrition, epigenetic alterations, defective proteostasis, and genomic instability. Given the widespread biological actions of CF6, the physiological and pathological actions of IF1 may be complex.