Eicosapentaenoic acid and oxypurinol in the treatment of muscle wasting in a mouse model of cancer cachexia

Cancer cachexia is a wasting condition, driven by systemic inflammation and oxidative stress. This study investigated eicosapentaenoic acid (EPA) in combination with oxypurinol as a treatment in a mouse model of cancer cachexia. Mice with cancer cachexia were randomized into 4 treatment groups (EPA (0.4 g/kg/day), oxypurinol (1 mmol/L ad-lib), combination, or control), and euthanized after 29 days. Analysis of oxidative damage to DNA, mRNA analysis of pro-oxidant, antioxidant and proteolytic pathway components, along with enzyme activity of pro- and antioxidants were completed on gastrocnemius muscle. The control group displayed earlier onset of tumor compared to EPA and oxypurinol groups (P&lt;0.001). The EPA group maintained body weight for an extended duration (20 days) compared to the oxypurinol (5 days) and combination (8 days) groups (P&lt;0.05). EPA (18.2&plusmn;3.2 pg/ml) and combination (18.4&plusmn;3.7 pg/ml) groups had significantly higher 8-OH-dG levels than the control group (12.9&plusmn;1.4 pg/ml, P&le;0.05) indicating increased oxidative damage to DNA. mRNA levels of GPx1, MURF1 and MAFbx were higher following EPA treatment compared to control (P&le;0.05). Whereas oxypurinol was associated with higher GPx1, MnSOD, CAT, XDH, MURF1, MAFbx and UbB mRNA compared to control (P&le;0.05). Activity of total SOD was higher in the oxypurinol group (32.2&plusmn;1.5 U/ml) compared to control (27.0&plusmn;1.3 U/ml, P&lt;0.01), GPx activity was lower in the EPA group (8.76&plusmn;2.0 U/ml) compared to control (14.0&plusmn;1.9 U/ml, P&lt;0.05), and catalase activity was lower in the combination group (14.4&plusmn;2.8 U/ml) compared to control (20.9&plusmn;2.0 U/ml, P&lt;0.01). There was no change in XO activity. The increased rate of weight decline in mice treated with oxypurinol indicates that XO may play a protective role during the progression of cancer cachexia, and its inhibition is detrimental to outcomes. In combination with EPA, there was little significant improvement from control, indicating oxypurinol is unlikely to be a viable treatment compound in cancer cachexia.<br /

Differential effects of dietary canola and soybean oil intake on oxidative stress in stroke-prone spontaneously hypertensive rats

Background: Canola oil shortens the life span of stroke-prone spontaneously hypertensive (SHRSP) rats compared with rats fed soybean oil when given as the sole dietary lipid source. One possible mechanism leading to the damage and deterioration of organs due to canola oil ingestion is oxidative stress. This study investigated the effect of canola oil intake on oxidative stress in this animal model.Method: Male SHRSP rats, were fed a defatted control diet containing 10% wt/wt soybean oil or a defatted treatment diet containing 10% wt/wt canola oil, and given water containing 1% NaCl. Blood pressure was measured weekly. Blood was collected prior to beginning the diets and at the end of completion of the study for analysis of red blood cell (RBC) antioxidant enzymes, RBC and plasma malondialdehyde (MDA), plasma 8- isoprostane and plasma lipids.Results: Canola oil ingestion significantly decreased the life span of SHRSP rats compared with soybean oil, 85.8 &plusmn; 1.1 and 98.3 &plusmn; 3.4 days, respectively. Systolic blood pressure increased over time with a significant difference between the diets at the 6th week of feeding. Canola oil ingestion significantly reduced RBC superoxide dismutase, glutathione peroxidase and catalase activities, total cholesterol and low-density lipoprotein cholesterol compared with soybean oil. There were no significant differences in RBC MDA concentration between canola oil fed and soybean oil fed rats. In contrast, plasma MDA and 8-isoprostane concentration was significantly lower in the canola oil group compared to the soybean oil group.Conclusion: In conclusion, canola oil ingestion shortens the life span of SHRSP rats and leads to changes in oxidative status, despite an improvement in the plasma lipids.<br /

The effect of cocoa supplementation on hepatic steatosis, reactive oxygen species and LFABP in a rat model of NASH

Background Non alcoholic steatohepatitis is hypothesised to develop via a mechanism involving fat accumulation and oxidative stress. The current study aimed to investigate if an increase in oxidative stress was associated with changes in the expression of liver fatty acid binding protein in a rat model of non alcoholic steatohepatitis and whether cocoa supplementation attenuated those changes. Methods Female Sprague Dawley rats were fed a high fat control diet, a high fat methionine choline deficient diet, or one of four 12.5% cocoa supplementation regimes in combination with the high fat methionine choline deficient diet. Results Liver fatty acid binding protein mRNA and protein levels were reduced in the liver of animals with fatty liver disease when compared to controls. Increased hepatic fat content was accompanied by higher levels of oxidative stress in animals with fatty liver disease when compared to controls. An inverse association was found between the levels of hepatic liver fatty acid binding protein and the level of hepatic oxidative stress in fatty liver disease. Elevated NADPH oxidase protein levels were detected in the liver of animals with increased severity in inflammation and fibrosis. Cocoa supplementation was associated with partial attenuation of these pathological changes, although the severity of liver disease induced by the methionine choline deficient diet prevented complete reversal of any disease associated changes. Red blood cell glutathione was increased by cocoa supplementation, whereas liver glutathione was reduced by cocoa compared to methionine choline deficient diet fed animals. Conclusion These findings suggest a potential role for liver fatty acid binding protein and NADPH oxidase in the development of non alcoholic steatohepatitis. Furthermore, cocoa supplementation may have be of therapeutic benefit in less sever forms of NASH

Decreased NADPH oxidase expression and antioxidant activity in cachectic skeletal muscle

Background - Cancer cachexia is the progressive loss of skeletal muscle protein that contributes significantly to cancer morbidity and mortality. Evidence of antioxidant attenuation and the presence of oxidised proteins in patients with cancer cachexia indicate a role for oxidative stress. The level of oxidative stress in tissues is determined by an imbalance between reactive oxygen species production and antioxidant activity. This study aimed to investigate the superoxide generating NADPH oxidase (NOX) enzyme and antioxidant enzyme systems in murine adenocarcinoma tumour-bearing cachectic mice. Methods - Superoxide levels, mRNA levels of NOX enzyme subunits and the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidise (GPx) and catalase was measured in the skeletal muscle of mice with cancer and cancer cachexia. Protein expression levels of NOX enzyme subunits and antioxidant enzyme activity was also measured in the same muscle samples. Results - Superoxide levels increased 1.4-fold in the muscle of mice with cancer cachexia, and this was associated with a decrease in mRNA of NOX enzyme subunits, NOX2, p40phox and p67phox along with the antioxidant enzymes SOD1, SOD2 and GPx. Cancer cachexia was also associated with a 1.3-fold decrease in SOD1 and 2.0-fold decrease in GPx enzyme activity. Conclusion - Despite increased superoxide levels in cachectic skeletal muscle, NOX enzyme subunits, NOX2, p40phox and p67phox, were downregulated along with the expression and activity of the antioxidant enzymes. Therefore, the increased superoxide levels in cachectic skeletal muscle may be attributed to the reduction in the activity of endogenous antioxidant enzymes

Pre-eclampsia and offspring cardiovascular health: mechanistic insights from experimental studies

Pre-eclampsia is increasingly recognized as more than an isolated disease of pregnancy. Women who have had a pregnancy complicated by pre-eclampsia have a 4-fold increased risk of later cardiovascular disease. Intriguingly, the offspring of affected pregnancies also have an increased risk of higher blood pressure and almost double the risk of stroke in later life. Experimental approaches to identify the key features of pre-eclampsia responsible for this programming of offspring cardiovascular health, or the key biological pathways modified in the offspring, have the potential to highlight novel targets for early primary prevention strategies. As pre-eclampsia occurs in 2–5% of all pregnancies, the findings are relevant to the current healthcare of up to 3 million people in the U.K. and 15 million people in the U.S.A. In the present paper, we review the current literature that concerns potential mechanisms for adverse cardiovascular programming in offspring exposed to pre-eclampsia, considering two major areas of investigation: first, experimental models that mimic features of the in utero environment characteristic of pre-eclampsia, and secondly, how, in humans, offspring cardiovascular phenotype is altered after exposure to pre-eclampsia. We compare and contrast the findings from these two bodies of work to develop insights into the likely key pathways of relevance. The present review and analysis highlights the pivotal role of long-term changes in vascular function and identifies areas of growing interest, specifically, response to hypoxia, immune modification, epigenetics and the anti-angiogenic in utero milieu

Strength Differential Measured in Inconel 718: Effects of Hydrostatic Pressure Studied

Aeropropulsion components, such as disks, blades, and shafts, are commonly subjected to multiaxial stress states at elevated temperatures. Experimental results from loadings as complex as those experienced in service are needed to help guide the development of accurate viscoplastic, multiaxial deformation models that can be used to improve the design of these components. During a recent study on multiaxial deformation (ref. 1) on a common aerospace material, Inconel 718, it was shown that the material in the aged state exhibits a strength differential effect (SDE), whereby the uniaxial compressive yield and subsequent flow behavior are significantly higher than those in uniaxial tension. Thus, this material cannot be described by a standard von Mises yield formulation. There have been other formulations postulated (ref. 2) that involve other combinations of the stress invariants, including the effect of hydrostatic stress. The question remained as to which invariants are necessary in the flow model. To capture the physical mechanisms occurring during deformation and reflect them in the plasticity formulation, researchers examined the flow of Inconel 718 under various amounts of hydrostatic stress to determine whether or not hydrostatic stress is needed in the formulation. Under NASA Grant NCC3-464, monitored by the NASA Glenn Research Center, a series of tensile tests were conducted at Case Western Reserve University on aged (precipitation hardened) Inconel 718 at 650 C and with superimposed hydrostatic pressure. Dogbone shaped tensile specimens (3-mm-diameter gauge by 16-mm gauge length) and cylindrical compression specimens (3-mm-diameter gauge by 6-mm gauge length) were strain gauged and loaded in a high-pressure testing apparatus. Hydrostatic pressures were obtained with argon and ranged from 210 to 630 MPa. The aged Inconel 718 showed a pronounced difference in the tension and compression yield strength (i.e., an SDE), as previously observed. Also, there were no significant effects of hydrostatic pressure on either the tensile and compressive yield strength (see the graph) or on the magnitude of the SDE. This behavior is not consistent with the pressure-dependent theory of the SDE, which postulates that the SDE is associated with pressure-dependent and/or internal friction dependent deformation associated with non-Schmid effects at the crystal level (refs. 3 and 4). Flow in Inconel 718 appears to be independent of hydrostatic pressure, suggesting that this invariant may be removed from the phenomenological constitutive model. As part of an ongoing effort to develop advanced constitutive models, Glenn s Life Prediction Branch coordinated this work with that of research on the multiaxial deformation behavior of Inconel 718 being conducted at Pennsylvania State University under NASA Grant NCC597

Comparative genome mapping of the deer mouse (Peromyscus maniculatus) reveals greater similarity to rat (Rattus norvegicus) than to the lab mouse (Mus musculus)

<p>Abstract</p> <p>Background</p> <p>Deer mice (<it>Peromyscus maniculatus</it>) and congeneric species are the most common North American mammals. They represent an emerging system for the genetic analyses of the physiological and behavioral bases of habitat adaptation. Phylogenetic evidence suggests a much more ancient divergence of <it>Peromyscus </it>from laboratory mice (<it>Mus</it>) and rats (<it>Rattus</it>) than that separating latter two. Nevertheless, early karyotypic analyses of the three groups suggest <it>Peromyscus </it>to be exhibit greater similarities with <it>Rattus </it>than with <it>Mus</it>.</p> <p>Results</p> <p>Comparative linkage mapping of an estimated 35% of the deer mouse genome was done with respect to the Rattus and Mus genomes. We particularly focused on regions that span synteny breakpoint regions between the rat and mouse genomes. The linkage analysis revealed the Peromyscus genome to have a higher degree of synteny and gene order conservation with the Rattus genome.</p> <p>Conclusion</p> <p>These data suggest that: 1. the <it>Rattus </it>and <it>Peromyscus </it>genomes more closely represent ancestral Muroid and rodent genomes than that of <it>Mus</it>. 2. the high level of genome rearrangement observed in Muroid rodents is especially pronounced in <it>Mus</it>. 3. evolution of genome organization can operate independently of more commonly assayed measures of genetic change (e.g. SNP frequency).</p

On non-existence of static vacuum black holes with degenerate components of the event horizon

We present a simple proof of the non-existence of degenerate components of the event horizon in static, vacuum, regular, four-dimensional black hole spacetimes. We discuss the generalisation to higher dimensions and the inclusion of a cosmological constant.Comment: latex2e, 9 pages in A