Bioelectrical impedance analysis-derived phase angle as a determinant of protein-energy wasting and frailty in maintenance hemodialysis patients: retrospective cohort study.

BACKGROUND: Phase angle (PA), measured by bioelectrical impedance analysis (BIA) has been studied as indicator of nutritional status or muscle function in hemodialysis (HD) patients. It remains unclear if the phase angle is associated protein-energy wasting (PEW) or frailty, which are common complication in hemodialysis patients. The aim of this study is to determine whether BIA-derived PA is a marker of PEW or frailty in HD patients. METHODS: This retrospective observational study included 116 adult HD patients (35% female, 64 ± 12 years of age) in a single dialysis center. Patients were classified according to the PA quartiles into four groups; 1) first quartile: PA < 3.7°, 2) second quartile: PA 3.7-4.1°, 3) third quartile: PA 4.2-4.9°and 4) forth quartile: PA ≥ 5.0°. International Society of Renal Nutrition and Metabolism (ISRNM) criteria and Japanese version of Cardiovascular Health Study (J-CHS) criteria were used to identify PEW and frailty. RESULTS: The lower PA group was associated with a greater risk of PEW (35% vs. 24% vs. 21% vs. 3%; p = 0.032), frailty (59% vs. 40% vs. 21% vs. 3%; p < 0.001). In multivariate logistic regression analysis, the first quartile group was at a significantly greater risk of both PEW and frailty compared with the fourth quartile group after adjusting for other confounding factors. CONCLUSIONS: Lower PA was associated with a greater risk of PEW and frailty in HD patients.

Effects of Intradialytic Resistance Exercise on Protein Energy Wasting, Physical Performance and Physical Activity in Ambulatory Patients on Dialysis: A Single-Center Preliminary Study in a Japanese Dialysis Facility.

Patients under hemodialysis present protein-energy wasting (PEW), which is related with higher mortality rates. The study aimed to determine whether intradialytic resistance exercise training could improve physical performance, physical activity, and PEW in hemodialysis patients. In single center study, 75 hemodialysis patients were enrolled in an intradialytic resistance exercise training consisting of 20 min of adapted leg press, with a gymnastic ball, 3 days/week, during 9 months on the same day of hemodialysis therapy. Physical performance by short physical performance battery (SPPB), physical activity by life space assessment (LSA), and PEW score based on the nomenclature proposed by the International Society of Renal Nutrition and Metabolism in 2008 were assessed at baseline and after 9 months. Intradialytic resistance exercise training significantly improved SPPB score, LSA score, and PEW score (all, P < 0.05). In addition, intradialytic resistance exercise training improved SPPB score in patients with moderate and severe PEW subgroups (P < 0.05), associated with reduced prevalence of the patients with moderate to severe PEW (53% vs. 36%, P < 0.05). Intradialytic resistance exercise training was safe and effective to improve physical performance, physical activity, and PEW in hemodialysis patients.

Terpendole E and its derivative inhibit STLC- and GSK-1-resistant Eg5.

Terpendole E is first natural product found to inhibit mitotic kinesin Eg5, but its inhibitory mechanism remains to be revealed. Here, we report the effects of terpendole E and 11ketopaspaline (a new natural terpendole E analogue) on the Eg5-microtubule interaction and in several Eg5 mutants. 11-Ketopaspaline is a shunt product from terpendole E, and it shows potent inhibitory activity against the microtubule-stimulated ATPase activity of Eg5. Unlike other Eg5 inhibitors, such as S-trityl-L-cysteine (STLC) and GSK-1, both terpendole E and 11-ketopaspaline only partially inhibited Eg5-microtubule interaction. Furthermore, terpendole E and 11-ketopaspaline inhibited several Eg5 mutants that are resistant to STLC (Eg5(D130A), Eg5(L214A)) or GSK-1 (Eg5(I299F), Eg5(A356T)), but with the same extent of inhibition against wild-type Eg5. Because Eg5(D130A) and Eg5(L214A) show cross-resistance to most known Eg5 inhibitors, which bind the L5 loop, these results suggest that terpendole E and its analogues have a different binding site and/or inhibitory mechanism to those for L5 loop-binding type Eg5 inhibitors.

Application of proteomic profiling based on 2D-DIGE for classification of compounds according to the mechanism of action.

The development of new anticancer agents derived from natural resources requires a rapid identification of their molecular mechanism of action. To make this step short, we have initiated the proteomic profiling of HeLa cells treated with anticancer drugs representing a wide spectrum of mechanisms of action using two-dimensional difference gel electrophoresis (2D-DIGE). Unique proteome patterns were observed in HeLa cells treated with the HSP90 inhibitor geldanamycin, and were similar to the patterns induced by radicicol, a structurally different HSP90 inhibitor. On the other hand, etoposide and ICRF-193, compounds claimed to be topoisomerase II inhibitors, showed different proteomic profiles, which reflect their different biological activities as revealed by cell-cycle analysis. Thus far, combined data from 19 compounds have allowed their successful classification by cluster analysis according to the mechanism of action.

Amphidinolide h, a potent cytotoxic macrolide, covalently binds on actin subdomain 4 and stabilizes actin filament.

The actin-targeting toxins have not only proven to be invaluable tools in studies of actin cytoskeleton structure and function but they also served as a foundation for a new class of anticancer drugs. Here, we describe that amphidinolide H (AmpH) targets actin cytoskeleton. AmpH induced multinucleated cells by disrupting actin organization in the cells, and the hyperpolymerization of purified actin into filaments of apparently normal morphology in vitro. AmpH covalently binds on actin, and the AmpH binding site is determined as Tyr200 of actin subdomain 4 by mass spectrometry and halo assay using the yeast harboring site-directed mutagenized actins. Time-lapse analyses showed that AmpH stimulated the formation of small actin-patches, followed by F-actin rearrangement into aggregates via the retraction of actin fibers. These results indicate that AmpH is a novel actin inhibitor that covalently binds on actin.