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Cardiotoxicity by doxorubicin predicts worse prognosis of patients. Accumulation of damaged DNA has been implicated in doxorubicin-induced cardiotoxicity. SIRT1, an NAD+-dependent histone/protein deacetylase, protects cells by deacetylating target proteins. We investigated whether SIRT1 counteracts doxorubicin-induced cardiotoxicity by mediating Ser139 phosphorylation of histone H2AX, a critical signal of the DNA damage response.Doxorubicin (5 mg/kg per week, x4) was administered to mice with intact SIRT1 (Sirt1f/f) and mice that lack SIRT1 activity in cardiomyocytes (Sirt1f/f; MHCcre/+). Reductions in left ventricular fractional shortening and ejection fraction by doxorubicin treatment were more severe in Sirt1f/f; MHCcre/+ than in Sirt1f/f. Myocardial expression level of type-B natriuretic peptide was 2.5-fold higher in Sirt1f/f; MHCcre/+ than in Sirt1f/f after doxorubicin treatment. Sirt1f/f; MHCcre/+ showed larger fibrotic areas and higher nitrotyrosine levels in the heart after doxorubicin treatment. Although doxorubicin-induced DNA damage evaluated by TUNEL staining was enhanced in Sirt1f/f; MHCcre/+, the myocardium from Sirt1f/f; MHCcre/+ showed blunted Ser139 phosphorylation of H2AX by doxorubicin treatment. In H9c2 cardiomyocytes, SIRT1 knockdown attenuated Ser139 phosphorylation of H2AX, increased DNA damage, and enhanced caspase-3 activation under doxorubicin treatment. Immunostaining revealed that acetylation level of H2AX at Lys5 was higher in hearts from Sirt1f/f; MHCcre/+. In H9c2 cells, acetyl-Lys5-H2AX level was increased by SIRT1 knockdown and reduced by SIRT1 overexpression. Ser139 phosphorylation in response to doxorubicin treatment was blunted in a mutant H2AX with substitution of Lys5 to Gln (K5Q) that mimics acetylated lysine compared with that in wild-type H2AX. Expression of K5Q-H2AX as well as S139A-H2AX, which cannot be phosphorylated at Ser139, augmented doxorubicin-induced caspase-3 activation. Treatment of mice with resveratrol, a SIRT1 activator, attenuated doxorubicin-induced cardiac dysfunction, which was associated with a reduction in acetyl-Lys5-H2AX level and a preserved phospho-Ser139-H2AX level.These findings suggest that SIRT1 counteracts doxorubicin-induced cardiotoxicity by mediating H2AX phosphorylation through its deacetylation in cardiomyocytes.Doxorubicin-induced cardiotoxicity limits the further use of doxorubicin for cancer treatment and determines prognosis of patients. This work shows for the first time the protective effect of SIRT1, an NAD+-dependent deacetylase, on doxorubicin-induced cardiotoxicity using a genetically modified mouse model. We identified histone H2AX as a target of SIRT1 for proper DNA damage response. Therefore, DNA repair by SIRT1 could be a potential therapeutic target to attenuate doxorubicin cardiotoxicity. SIRT1 activity may also help to predict a risk of developing cardiotoxicity in patients treated with doxorubicin.

Background The physiological and pathological significance of the arachnoid membrane (AM) is still unknown. In this study, we investigated various characteristics of the AM, focusing on the influence of inflammation and fibrosis. Methods Small pieces of AM sample were obtained during neurosurgical procedures from 74 cases. The clinical and pathological characteristics of the hyperplastic AM group (≥ 50 μm) and the non-hyperplastic AM group ( Results The median age of the patients in hyperplastic AM group was significantly older than that of the non-hyperplastic AM group. Moreover, the number of fibroblasts, CD68+ cells, CD86+ cells, and CD206+ cells in the hyperplastic AM group was significantly higher than that in the non-hyperplastic AM group. The AM thickness was significantly correlated to age and number of fibroblasts, CD68+ cells, CD86+ cells, and CD206+ cells. The thickness of the AM was significantly correlated to the messenger RNA expression levels of VEGFα (ρ = 0.337), and the VEGFα expression levels were significantly correlated with TGFβ and TNFα. Conclusions The AM hyperplasia was influenced by aging and could be a result of inflammation and fibrosis through cytokine secretion from the inflammatory cells and fibroblasts in the AM.

Resveratrol affords protection against reactive oxygen species (ROS)-related diseases via activation of SIRT1, an NAD+-dependent deacetylase. However, the low bioavailability of resveratrol limits its therapeutic applications. Since piceatannol is a hydroxyl analog of resveratrol with higher bioavailability, it could be an alternative to resveratrol. In this study, we compared the cytotoxicity, antioxidative activity, and mechanisms of cytoprotection of piceatannol with those of resveratrol. In C2C12 cells incubated with piceatannol, electrospray ionization mass spectrometry analysis showed that piceatannol was present in the intracellular fraction. A high concentration (50 μM) of piceatannol, but not resveratrol, induced mitochondrial depolarization and apoptosis. However, piceatannol at 10 μM inhibited the increase in mitochondrial ROS level induced by antimycin A, and this ROS reduction was greater than that by resveratrol. The reduction in hydrogen peroxide–induced ROS by piceatannol was also greater than that by resveratrol or vitamin C. Piceatannol reduced antimycin A–induced apoptosis more than did resveratrol. SIRT1 knockdown abolished the antiapoptotic activity of resveratrol, whereas it blocked only half of the antiapoptotic activity of piceatannol. Piceatannol, but not resveratrol, induced heme oxygenase-1 (HO1) expression, which was blocked by knockdown of the transcription factor NRF2, but not by SIRT1 knockdown. HO1 knockdown partially blocked the reduction of ROS by piceatannol. Furthermore, the antiapoptotic action of piceatannol was abolished by HO1 knockdown. Our results suggest that the therapeutic dose of piceatannol protects cells against mitochondrial ROS more than does resveratrol via SIRT1- and NRF2/HO1–dependent mechanisms. The activation of NRF2/HO1 could be an advantage of piceatannol compared with resveratrol for cytoprotection. Significance Statement This study showed that piceatannol and resveratrol were different in cytotoxicity, oxidant-scavenging activities, and mechanisms of cytoprotection. Protection by piceatannol against apoptosis induced by reactive oxygen species was superior to that by resveratrol. In addition to the sirtuin 1–dependent pathway, piceatannol exerted nuclear factor erythroid 2–related factor 2/heme oxygenase-1–mediated antioxidative and antiapoptotic effects, which could be an advantage of piceatannol compared with resveratrol.

Introduction: Accumulated DNA damage has been implicated in doxorubicin (DOX)-induced cardiotoxicity. We recently found that deletion of SIRT1, a histone deacetylase, in the cardiomyocyte worsens DOX-induced cardiac injury in mice. However, its molecular mechanism remains unclear. Ser139 phosphorylation of histone H2AX catalyzed by ATM (mutated in ataxia-telangiectasia) at the sites of DNA damage mediates DNA repair. Hypothesis: Deacetylation of H2AX by SIRT1 mediates DNA damage response and protects cardiomyocytes from DOX-induced injury. Methods and Results: Wild-type (WT) and tamoxifen-inducible cardiomyocyte-specific SIRT1 knockout (SIRT1 cKO) mice received DOX (4 IP injections of 5 mg/kg/week) or a vehicle. Immunoblotting showed that myocardial phospho-Ser139 H2AX level was increased by 1.6-fold in WT at 1 week after final DOX, but such a response was absent in SIRT1 cKO. Ser1981 phosphorylation of ATM by DOX were comparable in WT and SIRT1 cKO. The increase in TUNEL-positive nuclei by DOX was greater in SIRT1 cKO (0.13 to 0.38%) than WT (0.07 to 0.19%), suggesting higher DNA damage in SIRT1 cKO. In H9c2 cardiomyocytes, SIRT1 knockdown (KD) also abolished Ser139 phosphorylation of H2AX by DOX without changing phospho-ATM levels. Increases in DNA damage evaluated by the comet assay and cleavage of caspase-3 by DOX were also enhanced by SIRT1 KD. Immunostaining for acetyl-Lys5 H2AX in the heart sections revealed that acetyl-Lys5 H2AX levels were increased in SIRT1 cKO by 58% compared with WT. In H9c2 cells, acetyl-Lys5 H2AX level was also increased by SIRT1 KD and reduced by expression of wild-type SIRT1. In COS7 cells, a mutant in which Lys5 was substituted to glutamine (K5Q H2AX), a mimic of acetylated Lys5, showed attenuated Ser139 phosphorylation of H2AX by DOX. DOX-induced cleavage of caspase-3 was enhanced in H9c2 cells expressing K5Q H2AX as well as S139A H2AX, that cannot be phosphorylated at Ser139, compared with cells expressing WT H2AX. Conclusions: Aberrant Lys5 acetylation of H2AX via SIRT1 suppression interferes Ser139 phosphorylation, leading to accumulation of damaged DNA and promotion of the apoptotic response. Such regulation of the DNA damage response underlies protection by SIRT1 against DOX-induced cardiotoxicity.

Background Doxorubicin induces DNA damage not only in tumor cells but also in the cardiomyocyte, and accumulation of damaged DNA has been implicated in doxorubicin-induced cardiotoxicity. We previously found that cardiomyocyte-specific deletion of SIRT1, a NAD+-dependent histone/protein deacetylase, worsens doxorubicin-induced cardiotoxicity in mice. However, its molecular mechanism remains unclear. Phosphorylation of histone H2AX at Ser139 catalyzed by ATM (mutated in ataxia-telangiectasia) at the sites of DNA damage is a critical mediator for DNA repair. Purpose Here, we tested the hypothesis that deacetylation of H2AX by SIRT1 mediates DNA damage response to counteract doxorubicin-induced cardiotoxicity. Methods and results Wild-type (WT) mice and tamoxifen-inducible cardiomyocyte-specific SIRT1 knockout (SIRT1-cKO) mice at 3 month of age received doxorubicin (4 IP injections of 5 mg/kg/week) or a vehicle. Immunoblotting of myocardial lysates from mice 1 week after final doxorubicin showed that doxorubicin increased phospho-Ser139-H2AX level by 1.6-fold in WT, but such a response was blunted in SIRT1-cKO. Ser1981-phosphorylations of ATM induced by doxorubicin were similar in WT and SIRT1-cKO. DNA fragmentation evaluated by TUNEL staining revealed that the increase in TUNEL-positive nuclei by doxorubicin was more in SIRT1-cKO (0.13% to 0.38%) than those in WT (0.07% to 0.19%), suggesting higher DNA damage in SIRT1-cKO. In H9c2 cardiomyocytes, knockdown of SIRT1 also abolished the doxorubicin-induced Ser139-phosphorylation of H2AX without changing phospho-ATM levels. Increases in DNA damage evaluated by comet assay and cleavage of caspase-3 by doxorubicin were also enhanced in SIRT1-knockdown cells. Immunostaining for acetyl-Lys5-H2AX in the heart sections revealed that acetyl-Lys5-H2AX levels were increased in SIRT1-cKO by 58% compared with those in WT. In H9c2 cells, acetyl-Lys5-H2AX level was also increased by SIRT1 knockdown and reduced by expression of wild-type SIRT1. To test the role of the increased acetyl-Lys5-H2AX level under SIRT1 inhibition, we generated a mutant in which Lys5 was substituted to glutamine (K5Q H2AX) as a mimic of acetylated Lys5. In COS7 cells expressing WT or K5Q H2AX, Ser139-phosphorylation induced by doxorubicin was suppressed in K5Q mutant. In addition, doxorubicin-induced cleavage of caspase-3 was enhanced in H9c2 cells expressing K5Q H2AX as well as S139A H2AX, that cannot be phosphorylated at Ser139, compared with cells expressing WT H2AX. Conclusions These findings suggest that the increased Lys5 acetylation of H2AX via SIRT1 inhibition interferes Ser139 phosphorylation, leading to accumulation of damaged DNA and promotion of the apoptotic response. Such regulation of the DNA damage response contributes to protection by SIRT1 against doxorubicin-induced cardiotoxicity. Funding Acknowledgement Type of funding sources: None.

A high proportion of the sudden deaths among young individuals is attributable to anomalous aortic origin of a coronary artery. Among congenital heart diseases, the incidence of congenital coronary artery anomaly is approximately 1.3%. Herein, we report 2 surgical cases of anomalous aortic origin of a coronary artery.

Insulin-like growth factor (IGF)-binding proteins (IGFBPs) are secretory proteins that regulate IGF signaling. In this study, we investigated the role of IGFBP5 in replicative senescence in embryonic mouse fibroblasts (MEFs). During passages according to the 3T3 method, MEFs underwent senescence after the 5th passage (P5) based on cell growth arrest, an increase in the number of cells positive for senescence-associated β-galactosidase (SA-β-GAL) staining, and upregulation of p16 and p19. In P8 MEFs, IGFBP5 mRNA level was markedly reduced compared with that in P2 MEFs. Downregulation of IGFBP5 via siRNA in P2 MEFs increased the number of SA-β-GAL-positive cells, upregulated p16 and p19, and inhibited cell growth. Incubation of MEFs with IGFBP5 during serial passage increased the cumulative population doubling and decreased SA-β-GAL positivity compared with those in vehicle-treated cells. IGFBP5 knockdown in P2 MEFs increased phosphorylation levels of ERK1 and ERK2. Silencing of ERK2, but not that of ERK1, blocked the increase in the number of SA-β-GAL-positive cells in IGFBP5-knockdown cells. The reduction in the cell number and upregulation of p16 and p21 in IGFBP5-knockdown cells were attenuated by ERK2 knockdown. Our results suggest that downregulation of IGFBP5 during serial passage contributes to replicative senescence via ERK2 in MEFs.

We report a neonate with a successful percutaneous thrombectomy of a total thrombotic occlusion of the left pulmonary artery (LPA) after a surgical clipping for a patent ductus arteriosus (PDA). We suspected the compression of the LPA by the clipping and postoperative hemodynamic instability caused the LPA obstruction. After the surgical removal of the PDA clip and division of the PDA, we could safely retrieve the LPA thrombus with a non-hydrodynamic thrombectomy catheter for coronary arteries.

SIRT3 is a NAD+-dependent protein deacetylase localized in mitochondria. Although several previous studies reported cytoplasmic and/or nuclear localization of SIRT3, extra-mitochondrial SIRT3 was obscure. We found that mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs were expressed in the mouse brain and diffuse SIRT3 immunostaining in cytoplasm was detected in cultured neural cells and neural precursor cells where SIRT3 knockdown disturbed neural precursor cell differentiation. However, overexpression of SIRT3 in COS7 cells showed that expression levels of SIRT3ct was much lower than that of SIRT3mt. SIRT3ct but not SIRT3mt was promptly degraded by the ubiquitin-dependent degradation, in which SIRT3ct degradation was mediated mainly by the ubiquitination of NH2-terminal methionine and partly by that of lysine residues. SIRT3ct expression level was significantly enhanced by the treatment of cells with staurosporine or H2O2. H2O2 promoted nuclear translocation of SIRT3ct and induced histone H3 deacetylation and superoxide dismutase 2 expression. The overexpression of SIRT3ct decreased cell death by H2O2 at similar levels achieved by that of SIRT3mt. Knockdown of Sirt3 mRNA increased cell death by amyloid-b (Ab) and the overexpression of SIRT3ct opposed the toxic function of Ab in PC12 cells. These results indicated that SIRT3ct participated in cell survival under various stress conditions.

Background Failure of DNA repair and accumulation of damaged DNA have been implicated in the pathogenesis of doxorubicin-induced cardiotoxicity. SIRT1, an NAD+-dependent histone deacetylase, is known to positively regulate DNA repair. One of the earliest events in DNA damage response (DDR) is phosphorylation of histone H2AX on Ser139 catalyzed by kinases including ATM (mutated in ataxia-telangiectasia). However, it remains unknown whether SIRT1 protects the heart from doxorubicin-induced cardiotoxicity by regulating histone H2AX. Purpose In this study, we investigated whether SIRT1 plays a role against doxorubicin-induced cardiotoxicity by regulating histone H2AX and therefore DDR. Methods and results We used tamoxifen-inducible cardiomyocyte-specific SIRT1 knockout (SIRT1-cKO) mice. Knockout was induced at 2 month of age, and mice without Cre recombinase served as wild type (WT). Mice were treated with vehicle (Veh) or doxorubicin (4 IP injections of 5 mg/kg/week) starting at 3 month of age. Echocardiography showed that fractional shortening (FS) before doxorubicin was similar in WT (34%) and SIRT1-cKO (34%). However, FS at 1 week after final doxorubicin was lower in SIRT1-cKO than WT (26% vs. 30%, P In H9c2 cardiomyocytes, doxorubicin treatment (10 μM) increased both p-ATM and p-H2AX levels, but siRNA-mediated knockdown (KD) of SIRT1 attenuated doxorubicin-induced phosphorylation of H2AX without changing p-ATM level. Cell death after doxorubicin was enhanced in SIRT1-KD cells compared to control cells (13.2% vs 8.6%, P Conclusion These data suggest that SIRT1 plays a protective role against doxorubicin-induced cardiotoxicity via regulation of H2AX phosphorylation to mediates proper DDR. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Japan Society for the Promotion of Science

SIRT1 is a mammalian homologue of yeast longevity protein Sir2. SIRT1 deacetylates transcription factors, cofactors, and histones in an NAD+-dependent manner, and promotes cell survival, anti-oxidative function, and DNA repair. Although some studies have indicated that SIRT1 is involved in longevity, the function of SIRT1 for preventing aging and senescence is still unclear. In mouse embryonic fibroblasts (MEFs), we found that SIRT1 expression decreased by aging and IRT1 reciprocally regulated the expression level of Prl2C3, one of the prolactin-like peptides. In young MEFs, purified Prl2C3 inhibited the growth and increased the number of senescence-associated β galactosidase-positive cells with enlarged and flattened shapes. Moreover, immunostaining of human skin sections showed the expression of Prl2C3 in the basal cells of the epidermis. These results indicate that SIRT1 negatively regulates a senescence-associated protein rl2C3.

The glycosylation of pterostilbene by cultured plant cells of Phytolacca americana gave pterostilbene 4′- O-β-D-glucoside. Both pterostilbene and its 4- O-β-D-glucoside induced type XVII collagen expression in the EpiDermFT EFT-400 human skin cell model. Pterostilbene 4′- O-β-D-glucoside strongly induced type XVII collagen expression rather than pterostilbene.

Autophagy activation improves the phenotype in mdx mice, a Duchenne muscular dystrophy (DMD) model, although the underlying mechanisms are obscure. We previously found that resveratrol, a strong inducer of autophagy, ameliorates the cardiac pathology of mdx mice. Autophagy could eliminate damaged mitochondria, a major source of intracellular reactive oxygen species (ROS), although there is no evidence for mitochondriopathy in dystrophic cardiomyopathy. To elucidate resveratrol’s function, we investigated the deletion of mitochondrial DNA (mtDNA), autophagy of damaged mitochondria (mitophagy), and ROS accumulation in the mdx mouse heart. Low levels of normal mtDNA and abnormal accumulations of mitochondria-containing autophagosomes were found in the mdx mouse heart. Administering resveratrol to mdx mice for 56 weeks ameliorated the cardiomyopathy, with significant reductions in the amount of mtDNA deletion, the number of mitochondria-containing autophagosomes, and the ROS levels. Resveratrol induced nuclear FoxO3a accumulation and the expression of autophagy-related genes, which are targets of FoxOs. The most effective dose in mdx mice was 0.4 g resveratrol/kg food. In conclusion, resveratrol improved cardiomyopathy by promoting mitophagy in the mdx mouse heart. We propose that acquired mitochondriopathy worsens the pathology of DMD and is a potential therapeutic target for the cardiomyopathy in DMD patients.

Background: Cardiotoxicity of doxorubicin (DOX) is mediated through mitochondrial perturbations. SIRT1, an NAD + -dependent deacetylase, has been reported to promote cellular adaptation to metabolic imbalances in part via mitochondrial biogenesis. Hypothesis: SIRT1 in the cardiomyocyte counteracts DOX cardiotoxicity in vivo. Methods: Tamoxifen (Tam)-inducible cardiomyocyte-specific SIRT1 knockout mice (SIRT1 cKO) were used. At 2 months of age, mice received Tam to induce knockout, and mice without Cre recombinase served as wild type (WT). Both groups of mice were treated with DOX (4 IP injections of 5 mg/kg/week) starting at 3 months of age. Echocardiography was performed before and after DOX treatment. Cardiac tissues were sampled after the final DOX injection. H9c2 cardiomyocytes were used for in vitro analysis. Results: At baseline, there were no differences in left ventricular (LV) dimension, thickness, fractional shortening (FS), and ejection fraction (EF) between the groups. DOX significantly reduced FS, EF, and LV thickness in both groups of mice. However, FS and EF after DOX injections were lower in SIRT1 cKO than in WT (FS, 26% vs. 30%; EF, 59% vs. 65%, P Conclusions: The results suggested that SIRT1 in the cardiomyocyte counteracts DOX cardiotoxicity by preserving mitochondrial content in vivo. Enhanced degradation, but not impaired biogenesis, may be involved in mitochondrial depletion in SIRT1 cKO.

Mitochondrial autophagy eliminates damaged mitochondria and decreases reactive oxygen species (ROS). The autophagy inhibitor chloroquine (CQ) poten- tiates temozolomide (TMZ) cytotoxicity in glioma cells, but it is not known whether CQ does this by inhibiting mitochondrial autophagy. The effects of CQ and TMZ on MitoSOX Red fluorescence, a mitochondrial ROS indica- tor, and cell death were examined in rat C6 glioma cells. Mitochondrial autophagy was monitored by the colocal- ization of MitoTracker Red fluorescence and EGFP-LC3 dots. Mitochondrial content was measured by MitoTracker Green fluorescence and immunoblotting for a mitochon- drial protein. Finally, CQ's effects on tumor cells derived from a glioblastoma patient and human U87-MG glio- blastoma cells were assessed. TMZ (100-1,000 lM) alone did not affect mitochondrial ROS or cell death in C6 cells, but when administered with CQ (10 lM), it increased mitochondrial ROS and cell death. Antioxidants signifi- cantly suppressed the CQ-augmented cell death in TMZ- treated cells, indicating that mitochondrial ROS were involved in this cell death. TMZ treatment reduced Mito- Tracker Green fluorescence and mitochondrial protein levels, and these effects were inhibited by CQ. TMZ also increased the colocalization of EGFP-LC3 dots with mitochondria, and CQ enhanced this effect. CQ potentiated TMZ-induced cytotoxicity in patient-derived glioblastoma cells as well as human U87-MG glioblastoma cells. These results suggest that CQ increases cellular ROS and aug- ments TMZ cytotoxicity in glioma cells by inhibiting mitochondrial autophagy.

The first report dealt with the forward sliding and the backward tumbling as the most dangerous consequences of wheelchair use on board a passenger ship. The present paper proposes a dynamical model of wheelchair behaviour in an oscillatory environment. To simplify the movement of the wheelchair, a ball-caster is introduced in place of the ordinary caster wheel. A test dummy is used to eliminate the effect of human-body's intra- and inter-subject variability. Simultaneous differential equations expressing the wheelchair motions are solved by the 4th order Runge-Kutta method sequentially.A series of computer simulation is carried out for the wheelchair's motion on a flat and/or an inclined floor and the response in an oscillatory environment. The model proposed can also estimate the necessary driving torque to run along a given course. The effect of a movement of the centre of gravity was examined. A manually propelled wheelchair was assumed in this paper, and the model can be applied to a motorised wheelchair. The authors conclude that the proposed dynamical model is useful to estimate the wheelchair's response in an oscillatory environment quantitatively as well as qualitatively.

Experienced ship designers have been done the optimization of hull form and/or improvements of propulsive performance in the performance design procedure using their metaphysical information and analogized knowledge-process abilities based on their long-continued experiences. It may have been because that there have not been any formulations which make it possible to describe and evaluate the frame line configuration explicitly and quantitatively.In the second paper, the authors introduced a method for expressing and describing the frame line configuration using the Fourier Descriptors (FD), and showed that it is possible to describe almost all frame lines of ship's aft body and their small and fine changes. They also showed that FD is an appropriate method to express the relation between frame line configuration and self-propulsion factors.In the present paper, they discuss the effects of fine changes of frame line on the changes and improvements of self-propulsion factors (1-w) using the Fourier Descriptors. They show that the process of determining frame line configuration and its fine changes for improvements of self-propulsion factors that have been done intuitively and metaphysically by experienced ship designers are quite reasonable.

Ship form has been expressed using the “OFF-SETS” and “PRINCIPAL PARTICULARS (PRINCIPAL DIMENSIONS)” with “LINES” for about 100 years since the beginning of the modern developments of ship engineering/science.In the field of ship design, ship performance has been estimated and evaluated by means of indirect parameters such as principal dimensions and coefficients. Since these parameters do not give an unique ship form, ship designer has utilize their experience and intuition during the procedure of performance design for improving and determining the ship form. However, how long are we able to pass on the skilful knowledge to the future generation ?In the present paper, the authors propose a method for describing ship form by means of Fourier series called Fourier Descriptors (FD). They will show that FD can determine an arbitrary ship section uniquely and can decompose/reproduce arbitrary 2-dimensional ship section form.As the 1 st step of the performance evaluation, they show the effects of section form on the damping and added mass coefficients of 2-dimensional oscillating bodies that are commonly used in the ship motion estimation with comparing results obtained by means of Lewis Form transformation.

Measurements of physiological and psychological changes of subjects have been carried out under whole-body exposure to low frequency oscillations by using ship-motion simulator. Electroencephalogram, Electrocardiogram, facial expression, face surface temperature, are measured as the physiological effects, and symptoms of motion sickness or ride-quality are measured as the psychological effects. Methods for analyzing the measured results have been also developed. In this short monogram, results as well as methods of measurements, analyses are described.

Cardiomyopathy is the main cause of death in Duchenne muscular dystrophy. Here, we show that oral administration of resveratrol, which leads to activation of an NAD+-dependent protein deacetylase SIRT1, suppresses cardiac hypertrophy and fibrosis and restores cardiac diastolic function in dystrophin-deficient mdx mice. The pro-hypertrophic co-activator p300 protein but not p300 mRNA was up-regulated in the mdx heart, and resveratrol administration down-regulated the p300 protein level. In cultured cardiomyocytes, cardiomyocyte hypertrophy induced by the α1-agonist phenylephrine was inhibited by the overexpression of SIRT1 as well as resveratrol, both of which down-regulated p300 protein levels but not p300 mRNA levels. In addition, activation of atrial natriuretic peptide promoter by p300 was inhibited by SIRT1. We found that SIRT1 induced p300 down-regulation via the ubiquitin-proteasome pathway by deacetylation of lysine residues for ubiquitination. These findings indicate the pathological significance of p300 up-regulation in the dystrophic heart and indicate that SIRT1 activation has therapeutic potential for dystrophic cardiomyopathy. Background: Dystrophin deficiency leads to life-threatening cardiomyopathy, whereas cardiac p300 promotes cardiac hypertrophy/failure. Results: The SIRT1 activator resveratrol inhibited p300 protein up-regulation and attenuated cardiomyopathy in dystrophin-deficient mice, and SIRT1-induced p300 down-regulation was mediated via its deacetylation and ubiquitination. Conclusion: SIRT1 activation ameliorates dystrophic cardiomyopathy by targeting p300. Significance: Negative regulation of p300 is a novel cardioprotective mechanism of SIRT1.

Excessive reactive oxygen species (ROS) induce apoptosis and are associated with various diseases and with aging. SIRT1 (sirtuin-1), an NAD+-dependent protein deacetylase, decreases ROS levels and participates in cell survival under oxidative stress conditions. SIRT1 modulates the transcription factors p53, a tumor suppressor and inducer of apoptosis, and the forkhead O (FOXO) family, both of which play roles for cell survival and cell death. In this study, we aimed to know which is working greatly among p53 and FOXOs transcription factors in SIRT1’s cell protective functions under oxidative stress conditions. The antimycin A-induced increase in ROS levels and apoptosis was enhanced by SIRT1 inhibitors nicotinamide and splitomicin, whereas it was suppressed by a SIRT1 activator, resveratrol, and a SIRT1 cofactor, NAD+. SIRT1-siRNA abolished the effects of splitomicin and resveratrol. p53-knockdown experiment in C2C12 cells and experiment using p53-deficient HCT116 cells showed that splitomicin and resveratrol modulated apoptosis by p53-dependent and p53-independent pathways. In p53-independent cell protective pathway, we found that FOXO1, FOXO3a, and FOXO4 were involved in SOD2’s upregulation by resveratrol. The knockdown of these three FOXOs by siRNAs completely abolished the SOD2 induction, ROS reduction, and anti-apoptotic function of resveratrol. Our results indicate that FOXO1, FOXO3a and FOXO4, are indispensable for SIRT1-dependent cell survival against oxidative stress, although deacetylation of p53 has also some role for cell protective function of SIRT1.

Resveratrol ( trans -3,5,4′-trihydroxystilbene; RSV), a natural polyphenol, exerts a beneficial effect on health and diseases. RSV targets and activates the NAD + -dependent protein deacetylase SIRT1; in turn, SIRT1 induces an intracellular antioxidative mechanism by inducing mitochondrial superoxide dismutase (SOD2). Most RSV found in plants is glycosylated, and the effect of these glycosylated forms on SIRT1 has not been studied. In this study, we compared the effects of RSV and two glycosyl RSVs, resveratrol-3- O - β -d-glucoside (3G-RSV; polydatin/piceid) and resveratrol-4′- O - β -d-glucoside (4′G-RSV), at the cellular level. In oxygen radical absorbance capacity and 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays, the antioxidant activity of 3G-RSV was comparable to that of RSV, whereas the radical-scavenging efficiency of 4′G-RSV was less than 50% of that of RSV. However, 4′G-RSV, but not 3G-RSV, induced SIRT1-dependent histone H3 deacetylation and SOD2 expression in mouse C2C12 skeletal myoblasts; as with RSV, SIRT1 knockdown blunted these effects. RSV and 4′G-RSV, but not 3G-RSV, mitigated oxidative stress–induced cell death in C2C12 cells and primary neonatal rat cardiomyocytes. RSV and 4′G-RSV inhibited C2C12 cell proliferation, but 3G-RSV did not. RSV was found in both the intracellular and extracellular fractions of C2C12 cells that had been incubated with 4′G-RSV, indicating that 4′G-RSV was extracellularly deglycosylated to RSV, which was then taken up by the cells. C2C12 cells did not deglycosylate 3G-RSV. Our results point to 4′G-RSV as a useful RSV prodrug with high water solubility. These data also show that the in vitro antioxidative activity of these molecules did not correlate with their ability to protect cells from oxidative stress–induced apoptosis.