Impact of cardiac support device combined with slow-release prostacyclin agonist in a canine ischemic cardiomyopathy model

BackgroundThe cardiac support device supports the heart and mechanically reduces left ventricular (LV) diastolic wall stress. Although it has been shown to halt LV remodeling in dilated cardiomyopathy, its therapeutic efficacy is limited by its lack of biological effects. In contrast, the slow-release synthetic prostacyclin agonist ONO-1301 enhances reversal of LV remodeling through biological mechanisms such as angiogenesis and attenuation of fibrosis. We therefore hypothesized that ONO-1301 plus a cardiac support device might be beneficial for the treatment of ischemic cardiomyopathy.MethodsTwenty-four dogs with induced anterior wall infarction were assigned randomly to 1 of 4 groups at 1 week postinfarction as follows: cardiac support device alone, cardiac support device plus ONO-1301 (hybrid therapy), ONO-1301 alone, or sham control.ResultsAt 8 weeks post-infarction, LV wall stress was reduced significantly in the hybrid therapy group compared with the other groups. Myocardial blood flow, measured by positron emission tomography, and vascular density were significantly higher in the hybrid therapy group compared with the cardiac support device alone and sham groups. The hybrid therapy group also showed the least interstitial fibrosis, the greatest recovery of LV systolic and diastolic functions, assessed by multidetector computed tomography and cardiac catheterization, and the lowest plasma N-terminal pro-B-type natriuretic peptide levels (P < .05).ConclusionsThe combination of a cardiac support device and the prostacyclin agonist ONO-1301 elicited a greater reversal of LV remodeling than either treatment alone, suggesting the potential of this hybrid therapy for the clinical treatment of ischemia-induced heart failure

肺高血圧症に対するトロンボキサン合成阻害作用をもった新規長期作用型プロスタサイクリンアゴニストの経口投与

BACKGROUND: Continuous administration of prostacyclin has improved the survival of patients with pulmonary arterial hypertension (PAH). However, this treatment has some problems, including its short duration of activity and difficult delivery. Therefore, we developed ONO-1301, an orally active, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. METHODS AND RESULTS: We investigated whether oral administration of ONO-1301 can both prevent and reverse monocrotaline (MCT)-induced PAH in rats. Rats were randomly assigned to receive repeated oral administration of ONO-1301 twice daily beginning either 1 or 8 days after subcutaneous injection of MCT. A control group received oral saline, and a sham group received a subcutaneous injection of saline instead of MCT. MCT-treated controls developed significant pulmonary hypertension. Treatment with ONO-1301 from day 1 or 8 significantly attenuated the increases in right ventricular systolic pressure and the increase in medial wall thickness of pulmonary arterioles. Kaplan-Meier survival curves demonstrated that the effect of ONO-1301 was equivalent to that of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. A single oral dose of ONO-1301 increased plasma cAMP levels for up to 6h. Treatment with ONO-1301 significantly decreased urinary 11-dehydro-thromboxane B2 and increased the plasma hepatocyte growth factor concentration. CONCLUSIONS: Oral administration of ONO-1301 ameliorated PAH in rats, an effect that may occur through cAMP and hepatocyte growth factor.博士（医学）・乙1326号・平成26年3月17日日本循環器学会の許諾を得て登録（2014年6月6日付）ジャーナル公式サイト（日本循環器学会HP内）：https://www.j-circ.or.jp/journal/公開サイト（J-STAGE）：https://www.jstage.jst.go.jp/browse/circj

Exploring the 100 au Scale Structure of the Protobinary System NGC 2264 CMM3 with ALMA

We have observed the young protostellar system NGC 2264 CMM3 in the 1.3 mm and 2.0 mm bands at a resolution of about 0.1$"$ (70 au) with ALMA. The structures of two distinct components, CMM3A and CMM3B, are resolved in the continuum images of both bands. CMM3A has an elliptical structure extending along the direction almost perpendicular to the known outflow, while CMM3B reveals a round shape. We have fitted two 2D-Gaussian components to the elliptical structure of CMM3A and CMM3B, and have separated the disk and envelope components for each source. The spectral index $\alpha$ between 2.0 mm and 0.8 mm is derived to be 2.4-2.7 and 2.4-2.6 for CMM3A and CMM3B, respectively, indicating the optically thick dust emission and/or the grain growth. A velocity gradient in the disk/envelope direction is detected for CMM3A in the CH$_3$CN, CH$_3$OH, and $^{13}$CH$_3$OH lines detected in the 1.3 mm band, which can be interpreted as the rotation of the disk/envelope system. From this result, the protostellar mass of CMM3A is roughly evaluated to be $0.1- 0.5$ $M_\odot$ by assuming Keplerian rotation. The mass accretion rate is thus estimated to be $5\times10^{-5}$ - 4 $\times$ $10^{-3}$ $M_\odot$ yr$^{-1}$, which is higher than typical mass accretion rate of low-mass protostars. The OCS emission line shows a velocity gradient in both outflow direction and disk/envelope direction. A hint of outflow rotation is found, and the specific angular momentum of the outflow is estimated to be comparable to that of the disk. These results provide us with novel information on the initial stage of a binary/multiple system.Comment: Accepted for publication in the Astrophysical Journal, 21 pages, 12 figure

Rhotekin regulates axon regeneration through the talin-Vinculin-Vinexin axis in Caenorhabditis elegans.

Axon regeneration requires actomyosin interaction, which generates contractile force and pulls the regenerating axon forward. In Caenorhabditis elegans, TLN-1/talin promotes axon regeneration through multiple down-stream events. One is the activation of the PAT-3/integrin-RHO-1/RhoA GTPase-LET-502/ROCK (Rho-associated coiled-coil kinase)-regulatory non-muscle myosin light-chain (MLC) phosphorylation signaling pathway, which is dependent on the MLC scaffolding protein ALP-1/ALP-Enigma. The other is mediated by the F-actin-binding protein DEB-1/vinculin and is independent of the MLC phosphorylation pathway. In this study, we identified the svh-7/rtkn-1 gene, encoding a homolog of the RhoA-binding protein Rhotekin, as a regulator of axon regeneration in motor neurons. However, we found that RTKN-1 does not function in the RhoA-ROCK-MLC phosphorylation pathway in the regulation of axon regeneration. We show that RTKN-1 interacts with ALP-1 and the vinculin-binding protein SORB-1/vinexin, and that SORB-1 acts with DEB-1 to promote axon regeneration. Thus, RTKN-1 links the DEB-1-SORB-1 complex to ALP-1 and physically connects phosphorylated MLC on ALP-1 to the actin cytoskeleton. These results suggest that TLN-1 signaling pathways coordinate MLC phosphorylation and recruitment of phosphorylated MLC to the actin cytoskeleton during axon regeneration

ONO-1301, a Sustained-Release Prostacyclin Analog, Ameliorates the Renal Alterations in a Mouse Type 2 Diabetes Model Possibly Through Its Protective Effects on Mesangial Cells

Diabetic nephropathy is the most common pathological disorder predisposing patients to end-stage renal disease. Considering the increasing prevalence of type 2 diabetes mellitus worldwide, novel therapeutic approaches are urgently needed. ONO-1301 is a novel sustained-release prostacyclin analog that inhibits thromboxane A2 synthase. Here we examined the therapeutic effects of the intermittent administration of slow-release ONO-1301 (SR-ONO) on diabetic nephropathy in obese type 2 diabetes mice, as well as its direct effects on mesangial cells. The subcutaneous injection of SR-ONO (3mg/kg) every 3 wks did not affect the obesity or hyperglycemia in the db/db obese mice used as a model of type 2 diabetes, but it significantly ameliorated their albuminuria, glomerular hypertrophy, glomerular accumulation of type IV collagen, and monocyte/macrophage infiltration, and also the increase of TGF-β1, α-smooth muscle actin (α-SMA) and MCP-1 compared to vehicle treatment. In cultured mouse mesangial cells, ONO-1301 concentration-dependently suppressed the increases in TGF-β, type IV collagen, α-SMA, MCP-1 and fibronectin induced by high ambient glucose, at least partly through prostacyclin (PGI2) receptor-mediated signaling. Taken together, these results suggest the potential therapeutic efficacy of the intermittent administration of SR-ONO against type 2 diabetic nephropathy, possibly through protective effects on mesangial cells

Effects of hydrographic conditions on the transport of neon flying squid Ommastrephes bartramii larvae in the North Pacific Ocean

The neon flying squid, Ommastrephes bartramii, is widespread in subtropical and temperate regions. In the North Pacific Ocean, the species is comprised of two spawning cohorts; an autumn cohort and a winter-spring cohort. Interestingly, despite their apparently contiguous hatching periods, there is a marked disparity in the mantle length of both cohorts. We hypothesized that differences in the ambient temperature during larval development were responsible for the observed disparity in mantle size. Numerical simulations of ambient temperature revealed that water temperatures were approximately 1 °C higher in areas inhabited by the autumn cohort than they were in areas inhabited by the winter-spring cohort. The findings imply that differences in ambient water temperature and nutrient condition may be responsible for the observed differences in the growth of the autumn and winter-spring cohorts

Fuel reduction in coastal squid jigging boats equipped with various combinations of conventional metal halide lamps and low-energy LED panels

Application of the low-energy light emitting diode (LED) is considered as a possible measure for fuel saving in the squid jigging fishery. We monitored fuel consumption of 14 coastal squid jigging boats ranging in size from 6.6 to 19. gross tons (GT) operating in the northern and western waters of the Sea of Japan in 2009-2011. In summer in the northern waters, squid boats of 19. GT consumed approximately 900. l in one operation that lasted from the afternoon to the next morning and 54% of the fuel was used during jigging with 53 conventional metal halide lamps (MHs) of 159. kW in total. In winter in the western waters, the total amount of fuel consumed in conventional operations of the 6.6-16. GT boats was less, but fuel consumption during jigging with lamps accounted for 70-78% of the total consumption due to close fishing grounds. The relationship between fuel consumption (l) and energy (kW. h) during jigging with lamps was expressed as a linear regression containing effects of the boat size and the inherent character of each boat. Fuel consumption rate decreases on average 0.28. l/kW. h by using LEDs with a reduced number of MHs. When 9. kW LEDs were employed with 24. MHs for 19. GT boat in the western water in summer, 24% fuel saving was estimated