Project description:Background.More than 90 tyrosine kinases have been implicated in the pathogenesis of malignant transformation and tumor angiogenesis. Tyrosine kinase inhibitors (TKIs) have emerged as effective therapies in treating cancer by exploiting this kinase dependency. The tyrosine kinase inhibitor erlotinib targets epidermal growth factor receptor (EGFR), whereas sunitinib targets primarily vascular endothelial growth factor receptor (VEGRF) and platelet-derived growth factor receptor (PDGFR). TKIs impact the function of non-malignant cells had have on- and off-target toxicities, including cardiotoxicities. Most of the reports of sunitinib have identified cardiotoxic effects, whereas erlotinib was less often found to have these effects. We hypothesized that the deleterious effects of TKIs were related to their impact on cardiac metabolism. Methods. C57BL/6 mice (10/group) were treated with therapeutic doses of sunitinib (40 mg/kg), erlotinib (50 mg/kg), or vehicle daily for 2 weeks. Echocardiographic assessment of the heart in vivo identified significant systolic dysfunction consistent with cardiotoxicity compared to vehicle treated controls. Heart, skeletal muscle, liver, and serum were flash frozen and prepped for non-targeted GC-MS metabolomics analysis. Results. Compared to vehicle treated controls, sunitinib treated mice had significant decreases insystolic function, whereas erlotinib treated mice did not. Non-Targeted metabolomics analysis of heart identified identified significant decreases in Docosahexaenoic acid (DHA), Arachidonic Acid/Eicosapentaenoic acid (EPA), O-Phosphocolamine, and 6-Hydroxynicotinic acid after sunitinib treatment. DHA was significantly decreased in skeletal muscle (quadriceps femoris), with elevations in cholesterol were identified in liver and elevated ethanol amine in serum. In contrast, erlotinib affected only one metabolite elevated (spermidine significantly increased).Conclusions.Mice treated with sunitinib had exhibited systolic dysfunction within two weeks, with significantly lower heart and skeletal muscle levels of long chain omega-3 fatty acids docosahexaenoic acid (DHA), arachidonic acid (AA)/eicosapentaenoic acid (EPA) and increased serum O-Phosphocholine phospholipid. This is the first link between sunitinib-induced cardiotoxicity and depletion in the polyunsaturated fatty acids (PUFAs) and inflammatory mediators DHA and AA/EPA in the heart, possibly by affecting mitochondria function where they have vital roles on calcium channels.

Project description:BackgroundThe metabolic and physiologic responses to exercise are increasingly interesting, given that regular physical activity enhances antioxidant capacity, improves cardiac function, and protects against type 2 diabetes. The metabolic interactions between tissues and the heart illustrate a critical cross-talk we know little about.MethodsTo better understand the metabolic changes induced by exercise, we investigated skeletal muscle (plantaris, soleus), liver, serum, and heart from exercise trained (or sedentary control) animals in an established rat model of exercise-induced aerobic training via non-targeted GC-MS metabolomics.ResultsExercise-induced alterations in metabolites varied across tissues, with the soleus and serum affected the least. The alterations in the plantaris muscle and liver were most alike, with two metabolites increased in each (citric acid/isocitric acid and linoleic acid). Exercise training additionally altered nine other metabolites in the plantaris (C13 hydrocarbon, inosine/adenosine, fructose-6-phosphate, glucose-6-phosphate, 2-aminoadipic acid, heptadecanoic acid, stearic acid, alpha-tocopherol, and oleic acid). In the serum, we identified significantly decreased alpha-tocopherol levels, paralleling the increases identified in plantaris muscle. Eleven unique metabolites were increased in the heart, which were not affected in the other compartments (malic acid, serine, aspartic acid, myoinositol, glutamine, gluconic acid-6-phosphate, glutamic acid, pyrophosphate, campesterol, phosphoric acid, creatinine). These findings complement prior studies using targeted metabolomics approaches to determine the metabolic changes in exercise-trained human skeletal muscle. Specifically, exercise trained vastus lateralus biopsies had significantly increased linoleic acid, oleic acid, and stearic acid compared to the inactive groups, which were significantly increased in plantaris muscle in the present study.ConclusionsWhile increases in alpha-tocopherol have not been identified in muscle after exercise to our knowledge, the benefits of vitamin E (alpha-tocopherol) supplementation in attenuating exercise-induced muscle damage has been studied extensively. Skeletal muscle, liver, and the heart have primarily different metabolic changes, with few similar alterations and rare complementary alterations (alpha-tocopherol), which may illustrate the complexity of understanding exercise at the organismal level.

Project description:Background.More than 90 tyrosine kinases have been implicated in the pathogenesis of malignant transformation and tumor angiogenesis. Tyrosine kinase inhibitors (TKIs) have emerged as effective therapies in treating cancer by exploiting this kinase dependency. The tyrosine kinase inhibitor erlotinib targets epidermal growth factor receptor (EGFR), whereas sunitinib targets primarily vascular endothelial growth factor receptor (VEGRF) and platelet-derived growth factor receptor (PDGFR). TKIs impact the function of non-malignant cells had have on- and off-target toxicities, including cardiotoxicities. Most of the reports of sunitinib have identified cardiotoxic effects, whereas erlotinib was less often found to have these effects. We hypothesized that the deleterious effects of TKIs were related to their impact on cardiac metabolism. Methods. C57BL/6 mice (10/group) were treated with therapeutic doses of sunitinib (40 mg/kg), erlotinib (50 mg/kg), or vehicle daily for 2 weeks. Echocardiographic assessment of the heart in vivo identified significant systolic dysfunction consistent with cardiotoxicity compared to vehicle treated controls. Heart, skeletal muscle, liver, and serum were flash frozen and prepped for non-targeted GC-MS metabolomics analysis. Results. Compared to vehicle treated controls, sunitinib treated mice had significant decreases insystolic function, whereas erlotinib treated mice did not. Non-Targeted metabolomics analysis of heart identified identified significant decreases in Docosahexaenoic acid (DHA), Arachidonic Acid/Eicosapentaenoic acid (EPA), O-Phosphocolamine, and 6-Hydroxynicotinic acid after sunitinib treatment. DHA was significantly decreased in skeletal muscle (quadriceps femoris), with elevations in cholesterol were identified in liver and elevated ethanol amine in serum. In contrast, erlotinib affected only one metabolite elevated (spermidine significantly increased).Conclusions.Mice treated with sunitinib had exhibited systolic dysfunction within two weeks, with significantly lower heart and skeletal muscle levels of long chain omega-3 fatty acids docosahexaenoic acid (DHA), arachidonic acid (AA)/eicosapentaenoic acid (EPA) and increased serum O-Phosphocholine phospholipid. This is the first link between sunitinib-induced cardiotoxicity and depletion in the polyunsaturated fatty acids (PUFAs) and inflammatory mediators DHA and AA/EPA in the heart, possibly by affecting mitochondria function where they have vital roles on calcium channels.

Project description:IntroductionHypertensive nephrosclerosis is among the leading causes of end-stage renal disease, but its pathophysiology is poorly understood. We wanted to explore early metabolic changes using gene expression and targeted metabolomics analysis.MethodsWe analyzed gene expression in kidneys biopsied from 20 patients with nephrosclerosis and 31 healthy controls with an Affymetrix array. Thirty-one amino acids were measured by liquid chromatography coupled with mass spectrometry (LC-MS) in urine samples from 62 patients with clinical hypertensive nephrosclerosis and 33 age- and sex-matched healthy controls, and major findings were confirmed in an independent cohort of 45 cases and 15 controls.ResultsAmino acid catabolism and synthesis were strongly underexpressed in hypertensive nephrosclerosis (13- and 7-fold, respectively), and these patients also showed gene expression patterns indicating decreased fatty acid oxidation (12-fold) and increased interferon gamma (10-fold) and cellular defense response (8-fold). Metabolomics analysis revealed significant distribution differences in 11 amino acids in hypertensive nephrosclerosis, among them tyrosine, phenylalanine, dopamine, homocysteine, and serine, with 30% to 70% lower urine excretion. These findings were replicated in the independent cohort. Integrated gene-metabolite pathway analysis showed perturbations of renal dopamine biosynthesis. There were also significant differences in homocysteine/methionine homeostasis and the serine pathway, which have strong influence on 1-carbon metabolism. Several of these disturbances could be interconnected through reduced regeneration of tetrahydrofolate and tetrahydrobiopterin.ConclusionEarly hypertensive nephrosclerosis showed perturbations of intrarenal biosynthesis of dopamine, which regulates natriuresis and blood pressure. There were also disturbances in serine/glycine and methionine/homocysteine metabolism, which may contribute to endothelial dysfunction, atherosclerosis, and renal fibrosis.

Dataset Information

Non-Targeted Metabolomics Analysis of the Effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Muscle, Liver and Serum Metabolism In Vivo.

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Non-Targeted Metabolomics Analysis of the Effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Muscle, Liver and Serum Metabolism In Vivo.

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