Structural Effects of Fusicoccin upon Upregulation of 14-3-3-Phospholigand Interaction and Cytotoxic Activity.

Fusicoccins (FCs) exhibit various cellular activities in mammalian cells, but details of the mechanism of action are not fully understood. In this study, we synthesized two pairs of model derivatives of FCs differing only in the presence and absence of a 12-hydroxyl group and evaluated their binding to a 14-3-3 protein together with various mode 1 and mode 3 phosphopeptide ligands. Our results demonstrate that the 12-hydroxyl group hampers binding to 14-3-3 with mode 1 phospholigands, presumably due to steric repulsion with the i+2 residue. Furthermore, cell-based evaluations showed that only non-substituted FCs exhibit significant cytotoxicity and all 12-hydroxyl derivatives were inactive, demonstrating a clear correlation with their ability to form ternary complexes with 14-3-3 and a mode 1 ligand. These results suggest that binding to 14-3-3 and a partner protein(s) possessing a mode 1 sequence plays a role in the mechanism of action of 12-non-substituted FCs.

The Association of Bite Instability and Comorbidities in Elderly People.

Objective The purpose was to evaluate the association between bite instability and comorbidities, comprehensive geriatric evaluations, or disabilities in elderly people. Methods A dentist examined the oral function, such as the bite stability, number of teeth, and the use of dentures, in 119 patients (93 women, mean age: 86.7±7.8) in 2 nursing homes for the elderly. The association between the oral function and the prevalence of diseases, including hypertension, diabetes mellitus, and dementia, was analyzed. Results The median number of teeth was 0 [0, 4]. The patients were divided into a bite-stable group (n=78, 66%) and bite-unstable group (n=41, 34%). The prevalence of hypertension was significantly higher in the bite-stable group than in the bite-unstable group (83% vs. 63%, respectively; p=0.0149), whereas the prevalence of diabetes mellitus was significantly lower in the bite-stable group than in the bite-unstable group (10% vs. 27%, respectively; p=0.0190). The prevalence of a cognitive function decline was significantly lower in the bite-stable group as well (59% vs. 83%, p=0.0082). According to the simplified comprehensive geriatric assessment 7, the bite-stable group scored significantly higher for instrumental activities of daily living (ADL) than the bite-unstable group (54% vs. 24%, respectively; p=0.0021). A multivariate logistic regression analysis demonstrated that bite instability was independently correlated with hypertension, diabetes mellitus, and instrumental activities of daily living. Conclusion Bite instability was independently associated with a decreased prevalence of hypertension or increased prevalence of diabetes mellitus and low levels of instrumental ADL in the elderly.

Highly sensitive cardiac troponin T in heart failure: comparison with echocardiographic parameters and natriuretic peptides.

BACKGROUND: Circulating cardiac troponin T is a marker of cardiomyocyte injury, and predicts adverse outcomes in patients with chronic heart failure. However, the significance of highly sensitive cardiac troponin T (hs-TnT) in cardiac dysfunction remains uncertain. The purpose of this study is to evaluate the correlation between hs-TnT and echocardiographic parameters or natriuretic peptides in patients with heart failure. METHODS AND RESULTS: We analyzed 283 consecutive out- or in-patients who had B-type natriuretic peptide (BNP) ≥20 pg/mL and were examined by echocardiography (mean age 66.5±13.9 years old; 159 males). Hs-TnT, BNP, N-terminal pro-BNP (NT-proBNP), and creatinine levels were measured simultaneously. LVEDD (left ventricular end-diastolic dimension), LVEF (left ventricular ejection fraction), E', E/E', left ventricular (LV) Tei index, and right ventricular (RV) Tei index were determined with echocardiography. The linear regression analyses demonstrated that loghs-TnT correlated with LVEDD (R=0.242, p<0.0001), LVEF (R=-0.369, p<0.0001), E' (R=-0.447, p<0.0001), E/E' (R=0.364, p<0.0001), LV Tei index (R=0.303, p<0.0001), RV Tei index (R=0.443, p<0.0001), and estimated glomerular filtration rate (eGFR) (R=-0.489, p<0.0001). Using multiple variable regression analysis, loghs-TnT independently correlated with LVEF, E/E', RV Tei index, and eGFR. Furthermore, loghs-TnT significantly correlated with logBNP (R=0.567, p<0.0001) or logNT-proBNP (R=0.647, p<0.0001). Multiple variable regression analysis demonstrated that loghs-TnT independently correlated with logBNP, age, and eGFR, or with logNT-proBNP, age, sex, and eGFR. CONCLUSIONS: The hs-TnT correlated with cardiac dysfunction evaluated by echocardiography and natriuretic peptides in patients with heart failure. The elevation of hs-TnT levels in heart failure may represent cardiac dysfunction due to minor and ongoing myocardial injury.

Comparative study of therapeutic effects of short- and long-acting loop diuretics in outpatients with chronic heart failure (COLD-CHF).

BACKGROUND: Loop diuretics have two different classes with different duration of activity: short-acting such as furosemide (duration of activity, 6h) and long-acting such as azosemide (duration of activity, 10-12h). We conducted a multicenter, randomized, controlled trial in order to compare the therapeutic effects of azosemide, a long-acting loop diuretic, and furosemide, a short-acting one, on neurohumoral factors and cardiac function in outpatients with chronic heart failure (CHF). METHODS: We enrolled 98 patients with CHF who were receiving furosemide and an angiotensin-converting enzyme inhibitor, and they were randomly divided into furosemide (n=49) and azosemide (n=49) groups. The furosemide group continued furosemide at the same dosage, and the azosemide group switched from furosemide to azosemide. At baseline and after 3 months, we measured body weight, and levels of brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), norepinephrine, active renin, creatinine, blood urea nitrogen, sodium, potassium, and hematocrit. Chest X-ray and echocardiography were also performed. RESULTS: Body weight and plasma levels of BNP and ANP significantly decreased after 3 months in the azosemide group compared to the furosemide group. There were no significant differences in changes of levels of creatinine, blood urea nitrogen, sodium, potassium, hematocrit, norepinephrine, and active renin after 3 months between the furosemide and azosemide groups. Echocardiography and chest X-ray did not demonstrate significant differences between the two groups. CONCLUSIONS: Long-acting azosemide is suggested to be useful for the improvement of neurohumoral factors compared with short-acting furosemide in patients with CHF.