Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling

The "metabolic cocktail" comprising glucose-insulin-potassium administrated at reperfusion reduces infarct size in the in vivo rat heart. We propose that insulin is the major component mediating this protection and acts via Akt prosurvival signaling. This hypothesis was studied in isolated perfused rat hearts (measuring infarct size to area of risk [%]) subjected to 35 minutes regional myocardial ischemia and 2 hours reperfusion. Insulin administered at the onset of reperfusion attenuated infarct size by 45% versus control hearts (P<0.001). Insulin-mediated cardioprotection was found to be independent of the presence of glucose at reperfusion. Moreover, the cell survival benefit of insulin is temporally dependent, in that insulin administration from the onset of reperfusion and maintained for either 15 minutes or for the duration of reperfusion reduced infarct size. In contrast, protection was abrogated if insulin administration was delayed until 15 minutes into reperfusion. Pharmacological inhibition of both upstream and downstream signals in the Akt prosurvival pathway abolished the cardioprotective effects of insulin. Here coadministration of insulin with the tyrosine kinase inhibitor lavendustin A, the phosphatidylinositol3-kinase (PI3-kinase) inhibitor wortmannin, and mTOR/p70s6 kinase inhibitor rapamycin abolished cardioprotection. Steady-state levels of activated/phosphorylated Akt correlated with insulin administration. Finally, downstream prosurvival targets of Akt including p70s6 kinase and BAD were modulated by insulin. In conclusion, insulin administration at reperfusion reduces myocardial infarction, is dependent on early administration during reperfusion, and is mediated via Akt and p70s6 kinase dependent signaling pathway. Moreover, BAD is maintained in its inert phosphorylated state in response to insulin therapy

The interrelation between temperature regimes and fish size in juvenile Atlantic cod (Gadus morhua): effects on growth and feed conversion efficiency

The present paper describes the growth properties of juvenile Atlantic cod (Gadus morhua) reared at 7, 10, 13 and 16 °C, and a group reared under “temperature steps” i.e. with temperature reduced successively from 16 to 13 and 10 °C. Growth rate and feed conversion efficiency of juvenile Atlantic cod were significantly influenced by the interaction of temperature and fish size. Overall growth was highest in the 13 °C and the T-step groups but for different reasons, as the fish at 13 °C had 10% higher overall feeding intake compared to the T-step group, whereas the T-step had 8% higher feeding efficiency. After termination of the laboratory study the fish were reared in sea pens at ambient conditions for 17 months. The groups performed differently when reared at ambient conditions in the sea as the T-step group was 11.6, 11.5, 5.3 and 7.5% larger than 7, 10, 13 and 16 °C, respectively in June 2005. Optimal temperature for growth and feed conversion efficiency decreased with size, indicating an ontogenetic reduction in optimum temperature for growth with increasing size. The results suggest an optimum temperature for growth of juvenile Atlantic cod in the size range 5–50 g dropping from 14.7 °C for 5–10 g juvenile to 12.4 °C for 40–50 g juvenile. Moreover, a broader parabolic regression curve between growth, feed conversion efficiency and temperature as size increases, indicate increased temperature tolerance with size. The study confirms that juvenile cod exhibits ontogenetic variation in temperature optimum, which might partly explain different spatial distribution of juvenile and adult cod in ocean waters. Our study also indicates a physiological mechanism that might be linked to cod migrations as cod may maximize their feeding efficiency by active thermoregulation

Dietary red palm oil olein attenuates myocardial ischaemia/reperfusion injury: Effects on glutathione peroxidase transcription and extracellular signal-regulated kinases 1/2

Dietary red palm oil (RPO) supplementation offers protection against ischaemia/reperfusion injury. Several pathways have been suggested to convey this protection. Recently it has been shown that RPO supplementation increases glutathione peroxidase (GPX) activity in the myocardium, but the mechanism behind this increase in GPX activity remains unknown. Antioxidant activity is known to play a role in pro-survival kinase signaling. The involvement of extracellular signal regulated kinases (ERK) early in reperfusion gave different results in previous studies, depending upon the diet to which RPO was supplemented. The aims of this study were to investigate the effects of dietary RPO supplementation on ERK 1/2 phosphorylation and GPX1, GPX3 and GPX4 transcription. Male Wistar rats were randomly divided into two groups. 1) SRC control group fed a standard rat chow diet (SRC) for 6 weeks and 2) RPO experimental group fed a standard rat chow diet supplemented with 2 ml of RPO olein per day. After the feeding period, rats were sacrificed and hearts perfused on a working heart perfusion apparatus. Cardiac function was measured before and after ischaemia in order to determine aortic output recovery. Hearts were also freeze clamped at 20 min perfusion, 10 min reperfusion and 25 min reperfusion, in order to determine the level of ERK and phosphorylated ERK by Western blotting. Regulation of glutathione peroxidase mRNA was determined before ischaemia using real-time polymerase chain reaction (RT-PCR). RPO supplementation did not produce significant changes in GPX1 or GPX3 mRNA expression when compared to the SRC control group. The mRNA expression of GPX4 was significantly higher in the RPO supplemented group when compared to controls. ERK44 phosphorylation was significantly higher in the RPO supplemented group when compared to the control group at 20 min perfusion. Our results confirmed improved aortic output recovery in the RPO group, as reported in previous studies after ischaemia/ reperfusion injury. The minor changes found in ERK phosphorylation in this study may suggest that RPO has little effect on this pathway. However, the increase at baseline should be investigated further. Our findings also suggest that RPO may increase glutathione peroxidase activity, through up- regulation of the mRNA levels of GPX4

Dietary red palm oil protects the heart against the cytotoxic effects of anthracycline

Strong anti-neoplastic anthracyclines like daunorubicin (DNR) and doxorubicin (DOX) have high efficacy against systemic neoplasm and solid tumours. However, clinically, they cause chronic cardiomyopathy and congestive heart failure. Red palm oil (RPO) supplementation can protect the heart against ischemic injury. We therefore hypothesize that supplementation with RPO during chemotherapy may protect the heart. Control rats received a standard diet, and the experimental group received RPO in addition for 4weeks. Each group was subsequently injected with either saline or DNR over a 12-day period towards the end of 4weeks. Hearts were excised and perfused on a working heart system. Functional parameters were measured. Tissue samples were collected for analysis of mRNA and protein levels. DNR+RPO increased aortic output by 25% (p<0·05) compared with DNR only. Furthermore, DNR treatment significantly reduced tissue mRNA levels of superoxide dismutase 1 (SOD1) and nitric oxide synthase 1 (NOS1) compared with untreated controls. Protein expression of SOD1 followed the same pattern as mRNA levels. NOS1 protein levels were significantly increased in DNR treated rats when compared with untreated controls. In addition, DNR increased phosphorylation of p38 and Jun N-terminal kinase compared with untreated controls, whereas DNR+RPO completely counteracted this activation. DNR+RPO significantly up regulated the protein extracellular signal-regulated kinase 1 level compared with DNR only. In this model of DNR treatment, RPO is associated with stabilization of important antioxidant enzymes such NOS and SOD, and inhibition of the 'stress' induced mitogen-activated protein kinase pathways. Dietary RPO also maintained function, similar to control, in DNR treated hearts. Copyright © 2011 John Wiley & Sons, Ltd.Articl

Daunorubicin therapy is associated with upregulation of E3 ubiquitin ligases in the heart

Daunorubicin (DNR) and doxorubicin (DOX) are two of the most effective anthracycline drugs known for the treatment of systemic neoplasms and solid tumors. However, their clinical use is hampered due to profound cardiotoxicity. The mechanism by which DNR injures the heart remains to be fully elucidated. Recent reports have indicated that DOX activates ubiquitin proteasome-mediated degradation of specific transcription factors; however, no reports exist on the effect of DNR on the E3 ubiquitin ligases, MURF-1 (muscle ring finger 1) and MAFbx (muscle atrophy F-box). The aim of this study was to investigate the effect of DNR treatment on the protein and organelle degradation systems in the heart and to elucidate some of the signalling mechanisms involved. Adult rats were divided into two groups where one group received six intraperitoneal injections of 2 mg/kg DNR on alternate days and the other group received saline injections as control. Hearts were excised and perfused on a working heart system the day after the last injection and freeze-clamped for biochemical analysis. DNR treatment significantly attenuated cardiac function and increased apoptosis in the heart. DNR-induced cardiac cytotoxicity was associated with upregulation of the E3 ligases, MURF-1 and MAFbx and also caused significant increases in two markers of autophagy, beclin-1 and LC3. These changes observed in the heart were also associated with attenuation of the phosphoinositide 3-kinase/Akt signalling pathway. © 2012 by the Society for Experimental Biology and Medicine

Geographic variation in growth and food conversion efficiency of juvenile Atlantic halibut related to latitude

Item does not contain fulltex