14,15-Dihydroxyeicosatrienoic acid, a soluble epoxide hydrolase metabolite in blood, is a predictor of anthracycline-induced cardiotoxicity - a hypothesis generating study.

BACKGROUND: Early identification of patients susceptible to chemotherapy-induced cardiotoxicity could lead to targeted treatment to reduce cardiac dysfunction. Rats treated with doxorubicin (DOX), a chemotherapeutic agent, have increased cardiac expression of 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), a bioactive lipid implicated in hypertension and coronary artery disease. However, the utility of 14,15-DHET as plasma biomarkers was not defined. The aim of this study is to investigate if levels of 14,15-DHET are an early blood biomarker to predict the subsequent occurrence of cardiotoxicity in cancer patients after chemotherapy. METHODS: H9c2 rat cardiomyocytes were treated with DOX (1 µM) for 2 h and levels of 14,15-DHET in cell media was quantified at 2, 6 or 24 h in media after DOX treatment. Similarly, female Sprague-Dawley rats were treated with DOX for two weeks and levels of 14,15-DHET was assessed in plasma at 48 h and 2 weeks after DOX treatment. Changes in brain natriuretic peptide (BNP) mRNA, an early cardiac hypertrophy process, were determined in the H9c2 cells and rat cardiac tissue. Results were confirmed in human subjects by assessment of levels of 14,15-DHET in plasma of breast cancer patients before and after DOX treatment and left ventricular ejection fraction (LVEF), a clinical marker of cardiotoxicity. RESULTS: Levels of 14,15-DHET in cell media and rat plasma increased ~ 3-fold and was accompanied with increase in BNP mRNA in H9c2 cells and rat cardiac tissue after DOX treatment. In matched plasma samples from breast cancer patients, levels of 14,15-DHET were increased in patients that developed cardiotoxicity at 3 months before occurrence of LVEF decrease. CONCLUSIONS: Together, these results indicate that levels of 14,15-DHET are elevated prior to major changes in cardiac structure and function after exposure to anthracyclines. Increased levels of 14,15-DHET in plasma may be an important clinical biomarker for early detection of anthracycline-induced cardiotoxicity in cancer patients.

Metabolically healthy obese vs. Metabolic syndrome - The crosslink between nutritional exposure to bisphenols and physical exercise.

Obesity has become a worldwide pandemic as well as a major contributing factor to the increasing rate of type 2 diabetes (T2D). However, there is an intriguing variance demonstrated by a subset of obesity defined as metabolically healthy obesity (MHO). MHO individuals are less prone to develop obesity-related metabolic complications, such as metabolic syndrome (MetS) and further T2D. The exact reason why an MHO person does not present the cluster of risk factors associated with insulin resistance is unknown due to the challenge to mimic MHO in experimental settings. However, MHO individuals present lower sedentary behaviors in comparison to individuals with MetS, which might indicate that an adaptation to skeletal muscle, such as increased insulin sensitivity and glucose transporter (GLUT4), could play a major role in their healthy characteristics. The hypothesis invoked in this paper is that lower exposure to bisphenol together with increased levels of physical exercise underlie the physiological aspects behind MHO characteristics. Evidence suggests that exposure to "obseogens," such as bisphenol A (BPA), appears to impair insulin secretion and insulin response in cells containing GLUT4. Epidemiological studies have associated higher levels of BPA, as well as bisphenol S and F, in children with a risk for MetS development. Therefore, the combination between low bisphenol exposure and increased physical exercise may not necessarily affect body weight, but it could modify several metabolic pathways inhibiting insulin resistance, which characterize the heathy status of the MHO. If confirmed, this hypothesis could lead to therapeutic approaches to reverse MetS and inhibit T2D onset.

Levels of plasma glycan-binding auto-IgG biomarkers improve the accuracy of prostate cancer diagnosis.

Strategies to improve the early diagnosis of prostate cancer will provide opportunities for earlier intervention. The blood-based prostate-specific antigen (PSA) assay is widely used for prostate cancer diagnosis but specificity of the assay is not satisfactory. An algorithm based on serum levels of PSA combined with other serum biomarkers may significantly improve prostate cancer diagnosis. Plasma glycan-binding IgG/IgM studies suggested that glycan patterns differ between normal and tumor cells. We hypothesize that in prostate cancer glycoproteins or glycolipids are secreted from tumor tissues into the blood and induce auto-immunoglobulin (Ig) production. A 24-glycan microarray and a 5-glycan subarray were developed using plasma samples obtained from 35 prostate cancer patients and 54 healthy subjects to identify glycan-binding auto-IgGs. Neu5Acα2-8Neu5Acα2-8Neu5Acα (G81)-binding auto-IgG was higher in prostate cancer samples and, when levels of G81-binding auto-IgG and growth differentiation factor-15 (GDF-15 or NAG-1) were combined with levels of PSA, the prediction rate of prostate cancer increased from 78.2% to 86.2% than with PSA levels alone. The G81 glycan-binding auto-IgG fraction was isolated from plasma samples using G81 glycan-affinity chromatography and identified by N-terminal sequencing of the 50 kDa heavy chain variable region of the IgG. G81 glycan-binding 25 kDa fibroblast growth factor-1 (FGF1) fragment was also identified by N-terminal sequencing. Our results demonstrated that a multiplex diagnostic combining G81 glycan-binding auto-IgG, GDF-15/NAG-1 and PSA (≥ 2.1 ng PSA/ml for cancer) increased the specificity of prostate cancer diagnosis by 8%. The multiplex assessment could improve the early diagnosis of prostate cancer thereby allowing the prompt delivery of prostate cancer treatment.

Transcription of mtDNA and dyslipidemia are ameliorated by aerobic exercise in type 2 diabetes.

Physical inactivity and unhealthy food intake are strongly associated with the growing prevalence of type 2 diabetes (T2D). Dyslipidemia, a characteristic of T2D patient, contributes to an increase in intra-myocellular lipid accumulation and mitochondria dysfunction, in skeletal muscle cells and further to insulin resistance. The aim of this study was to evaluate the effect of aerobic exercise on dyslipidemia, mitochondrial homeostasis and mitochondrial DNA (mtDNA) transcription in T2D- induced animals. Wistar rats (8 weeks old) were fed a diet containing 60% fat over 9 weeks, at day 14 a single injection of STZ (25 mg/kg) was administered (T2D-induced). At week 3 of the experiment half of the animals started on an aerobic exercise 5-days/week. Blood and soleus muscle were collected at 9th experimental week. Abdominal fat, blood glucose, triglyceride, low-density-lipoprotein and high-density lipoprotein (HDL), and cellular mtDNA copy number, cytochrome b (cytb) mRNA and 8-isoprostane were measured. T2D-induced animals exhibited changes in blood glucose, weight gain, abdominal fat, LDL and muscular 8-isoprostane, mtDNA copy number and cytb mRNA. Aerobic exercise attenuated the increase in weight gain and abdominal fat and the decreased cytb mRNA, and increased HDL. Our results suggest that aerobic exercise might not affect all characteristics related to the development of T2D in the same way. However, since T2D is a multifactorial disease, improvement in parameters such as HDL levels, abdominal fat and weight gain induced by aerobic exercise might delay or inhibit the onset of T2D.

The role of mitochondrial DNA damage at skeletal muscle oxidative stress on the development of type 2 diabetes.

Reduced cellular response to insulin in skeletal muscle is one of the major components of the development of type 2 diabetes (T2D). Mitochondrial dysfunction involves in the accumulation of toxic reactive oxygen species (ROS) that leads to insulin resistance. The aim of this study was to verify the involvement of mitochondrial DNA damage at ROS generation in skeletal muscle during development of T2D. Wistar rats were fed a diet containing 60% fat over 8 weeks and at day 14 a single injection of STZ (25 mg/kg) was administered (T2D-induced). Control rats received standard food and an injection of citrate buffer. Blood and soleus muscle were collected. Abdominal fat was quantified as well as glucose, triglyceride, LDL, HDL, and total cholesterol in plasma and mtDNA copy number, cytochrome b (cytb) mRNA, 8-hydroxyguanosine, and 8-isoprostane (a marker of ROS) in soleus muscle. T2D-induced animal presented similar characteristics to humans that develop T2D such as changes in blood glucose, abdominal fat, LDL, HDL and cholesterol total. In soleus muscle 8-isoprostane, mtDNA copy number and 8-hydroxyguanosine were increased, while cytb mRNA was decreased in T2D. Our results suggest that in the development of T2D, when risks factors of T2D are present, intracellular oxidative stress increases in skeletal muscle and is associated with a decrease in cytb transcription. To overcome this process mtDNA increased but due to the proximity of ROS generation, mtDNA remains damaged by oxidation leading to an increase in ROS in a vicious cycle accounting to the development of insulin resistance and further T2D.

The effect of exercise on skeletal muscle glucose uptake in type 2 diabetes: An epigenetic perspective.

Changes in eating habits and sedentary lifestyle are main contributors to type 2 diabetes (T2D) development, and studies suggest that epigenetic modifications are involved with the growing incidence of this disease. Regular exercise modulates many intracellular pathways improving insulin resistance and glucose uptake in skeletal muscle, both early abnormalities of T2D. Mitochondria dysfunction and decreased expression of glucose transporter (GLUT4) were identified as main factors of insulin resistance. Moreover, it has been suggested that skeletal muscle of T2D subjects have a different pattern of epigenetic marks on the promoter of GLUT4 and PGC1, main regulator of mitochondrial function, compared with nondiabetic individuals. Recent studies have proposed that regular exercise could improve glucose uptake by the attenuation of such epigenetic modification induced at GLUT4, PGC1 and its downstream regulators; however, the exact mechanism is still to be understood. Herein we review the known epigenetic modifications on GLUT4 and mitochondrial proteins that lead to impairment of skeletal muscle glucose uptake and T2D development, and the effect of physical exercise at these modifications.