The xanthine oxidase inhibitor oxypurinol reduces cancer cachexia-induced cardiomyopathy

Springer, Jochen; Tschirner, Anika; Hartman, Kai; Haehling, Stephan von; Anker, Stefan D.; Doehner, Wolfram

doi:10.1016/j.ijcard.2013.05.063

Cited by 37 publications

(14 citation statements)

References 22 publications

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“…In addition to mitochondria, xanthine oxidase can generate ROS. Accordingly, inhibition of xanthine oxidase reduces cardiac atrophy and maintains heart function in rats inoculated with AH-130 Yoshida hepatoma cells (54). This further demonstrates the role of ROS overproduction in cardiac cachexia.…”

Section: Mechanisms Initiating Cardiac Cachexia During Cancermentioning

confidence: 64%

Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity

2017

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Cachexia is a wasting syndrome observed in many patients suffering from several chronic diseases including cancer. In addition to the progressive loss of skeletal muscle mass, cancer cachexia results in cardiac function impairment. During the severe stage of the disease, patients as well as animals bearing cancer cells display cardiac atrophy. Cardiac energy metabolism is also impeded with disruption of mitochondrial homeostasis and reduced oxidative capacity, although the available data remain equivocal. The release of inflammatory cytokines by tumor is a key mechanism in the initiation of heart failure. Oxidative stress, which results from the combination of chemotherapy, inadequate antioxidant consumption and chronic inflammation, will further foster heart failure. Protein catabolism is due to the concomitant activation of proteolytic systems and inhibition of protein synthesis, both processes being triggered by the deactivation of the Akt/mammalian target of rapamycin pathway. The reduction in oxidative capacity involves AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1α dysregulation. The nuclear factor-κB transcription factor plays a prominent role in the coordination of these alterations. Physical exercise appears as an interesting non-pharmaceutical way to counteract cancer cachexia-induced-heart failure. Indeed, aerobic training has anti-inflammatory effects, increases anti-oxidant defenses, prevents atrophy and promotes oxidative metabolism. The present review points out the importance of better understanding the concurrent structural and metabolic changes within the myocardium during cancer and the protective effects of exercise against cardiac cachexia.

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Section: Mechanisms Initiating Cardiac Cachexia During Cancermentioning

confidence: 64%

Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity

2017

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“…To our knowledge, this is the only pre-clinical data to support a link between hyperuricemia and cardiac diastolic dysfunction in rodents fed a western diet. 27, 28 The western diet employed in this investigation reflects the increased carbohydrate, as well as fat that is often consumed in western cultures and thus is very translationally relevant.…”

Section: Discussionmentioning

confidence: 99%

Uric Acid Promotes Left Ventricular Diastolic Dysfunction in Mice Fed a Western Diet

et al. 2015

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The rising obesity rates parallel increased consumption of a western diet, high in fat and fructose, which is associated with increased uric acid. Population based data support that elevated serum uric acids are associated with left ventricular hypertrophy and diastolic dysfunction. However, the mechanism by which excess uric acid promotes these maladaptive cardiac effects has not been explored. In assessing the role of western diet-induced increases in uric acid, we hypothesized that reductions in uric acid would prevent western diet-induced development of cardiomyocyte hypertrophy, cardiac stiffness and impaired diastolic relaxation by reducing growth and pro-fibrotic signaling pathways. Four week-old C57BL6/J male mice were fed excess fat (46%) and fructose (17.5%) with or without allopurinol (125mg/L), a xanthine oxidase inhibitor, for 16 weeks. The western diet induced increases in serum uric acid along with increases in cardiac tissue xanthine oxidase activity temporally related to increases in body weight, fat mass, and insulin resistance without changes in blood pressure. The western diet induced cardiomyocte hypertrophy, myocardial oxidative stress, interstitial fibrosis, and impaired diastolic relaxation. Further, the western diet enhanced activation of the S6 kinase-1 growth pathway and the pro-fibrotic transforming growth factor (TGF)-β1/Smad2/3 signaling pathway, and macrophage pro-inflammatory polarization. All results improved with allopurinol treatment, which lowered cardiac xanthine oxidase as well as serum uric acid levels. These findings support the notion that increased production of uric acid with intake of a western diet, promotes cardiomyocyte hypertrophy, inflammation and oxidative stress that lead to myocardial fibrosis and associated impaired diastolic relaxation.

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“…Hypoxanthine is the direct precursor of xanthine, but the xanthine oxidase reaction is inhibited by arsenite (George and Bray, 1983;Hille et al, 1983). Oxypurinol is another precursor of hypoxanthine (Sokol et al, 1998;Boer et al, 2004;Springer et al, 2013) and it was found by NMR to be increased (Table 2). An increase in both xanthine oxidase inhibitors is consistent with the significant decrease in xanthine ( Table 2).…”

Section: Discussionmentioning

confidence: 99%

Metabolic response of Agrobacterium tumefaciens 5A to arsenite

Tokmina‐Lukaszewska

Shi

Tripet

et al. 2017

Environmental Microbiology

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Wide-spread abundance in soil and water, coupled with high toxicity have put arsenic at the top of the list of environmental contaminants. Early studies demonstrated that both concentration and the valence state of inorganic arsenic (arsenite, As(III) vs. arsenate As(V)) can be modulated by microbes. Using genetics, transcriptomic and proteomic techniques, microbe-arsenic detoxification, respiratory As(V) reduction and As(III) oxidation have since been examined. The effect of arsenic exposure on whole-cell intracellular microbial metabolism, however, has not been extensively studied. We combined LC-MS and H NMR to quantify metabolic changes in Agrobacterium tumefaciens (strain 5A) upon exposure to sub-lethal concentrations of As(III). Metabolomics analysis reveals global differences in metabolite concentrations between control and As(III) exposure groups, with significant perturbations to intermediates shuttling into and cycling within the TCA cycle. These data are most consistent with the disruption of two key TCA cycle enzymes, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. Glycolysis also appeared altered following As(III) stress, with carbon accumulating as complex saccharides. These observations suggest that an important consequence of As(III) contamination in nature will be to alter microbial carbon metabolism at the microbial community level and thus has the potential to foundationally impact all biogeochemical cycles in the environment.

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The xanthine oxidase inhibitor oxypurinol reduces cancer cachexia-induced cardiomyopathy

Cited by 37 publications

References 22 publications

Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity

Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity

Uric Acid Promotes Left Ventricular Diastolic Dysfunction in Mice Fed a Western Diet

Metabolic response of Agrobacterium tumefaciens 5A to arsenite

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