Stigate the pathophysiology of cardiac damage and develop novel pharmacotherapy and preventative measures for MS. IR is defined as a state of reduced responsiveness to normal circulating 10781694 levels of insulin and plays a major role in the development of MS [18,2,19,20]. Thus we propose that IR is a key therapeutic target for the treatment and prevention of MS. Recent reports have linked the relation between obesity and IR in two different ways. First, ectopic lipid accumulation is a potential mechanism for this relationship. Second, a systemic chronic inflammatory response in obesity, characterized by alteredFigure 7. Expression of IL-6, TNF-a, ICAM-1, Collagen I/III and TGF-b1 mRNA in the heart. mRNA levels were detected by real-time PCR and each bar represented the mean 6SD. **P,0.01, *P,0.05 vs. NC; ##P,0.01, #P,0.05 vs. MS. NC group (n = 10); MS group (n = 10); MS+A group (n = 11); MS+H group (n = 11). doi:10.1371/journal.pone.0067530.gHuan-Lian-Jie-Du-Tang for Cardiac Damages in RatsFigure 8. The activation of SOCS3, phospho-JNK, phospho- AKT and serine phospho- IRS1 in the heart. The left panels showed representative blots of the left ventricular. The right bar graph showed relative protein levels. Each bar represented the mean 6SD. **P,0.01, *P,0.05 vs. NC; ##P,0.01, #P,0.05 vs. MS. NC group (n = 10); MS group (n = 10); 16985061 MS+A group (n = 11); MS+H group (n = 11). doi:10.1371/journal.pone.0067530.gcytokine production and activation of inflammatory signaling pathways, is another mechanism [21]. In a chronic inflammatory response of MS, inflammatory cytokines such as TNF-a, IL-1 and IL-6 were activated [4]. In addition, in adipose tissue of obese rodents and humans, TNF-a expression is increased [22], and reducing TNF-a expression could reduce IR in obese rodents [23]. Inflammation-mediated IR implicates several pathways including IKKb/NF-kB, JNK and SOCS3, which are activated by inflammatory cytokines. Many studies demonstrated that inhibiting the activity of IKK, JNK and SOCS3 by pharmacological inhibition or gene FD&C Yellow 5 knockout could improve IR [8,24?7,9]. In our study, the expression of inflammatory cytokines such as TNF-a, IL-1, and IL-6 was inhibited by pharmacological inhibitions, resulting in improving IR. Taken together, these results suggest that aberrant inflammation pathways may contribute to the onset of IR in MS rats. Insulin signaling pathway in metabolism is regulated by the insulin-stimulated tyrosine phosphorylation of IRS-1 and the activity of PI3-kinase/AKT signaling pathway. The PI3Kdependent activation of the AKT kinase is known to control programmed cell death and cellular metabolism [28]. Moreover, activated AKT could preserve cardiac function because in rodent models of myocardial infarction, bone marrow erived mesenchymal stem cells expressing constitutively activated AKT could enhance cardiomyocytes survival and organ function [29]. In our study, there were significant differences of left ventricle (LV) between the obese-fed and normal-fed rats, including LV structure (IVS and LVPW), diastolic function (A wave and E/A), and myocardial composition (the amount of collagen I/III). These differences were associated with reduced PI 3-kinase/AKT pathway. These results suggest that a long exposure to the obese-diet could inhibit insulin signaling, Anlotinib site thereby inducing myocardial damage on both cardiac structure and function. The efficacy of aspirin (acetylsalicylic acid) on reducing serine phosphorylation of IRS-1 associated wit.Stigate the pathophysiology of cardiac damage and develop novel pharmacotherapy and preventative measures for MS. IR is defined as a state of reduced responsiveness to normal circulating 10781694 levels of insulin and plays a major role in the development of MS [18,2,19,20]. Thus we propose that IR is a key therapeutic target for the treatment and prevention of MS. Recent reports have linked the relation between obesity and IR in two different ways. First, ectopic lipid accumulation is a potential mechanism for this relationship. Second, a systemic chronic inflammatory response in obesity, characterized by alteredFigure 7. Expression of IL-6, TNF-a, ICAM-1, Collagen I/III and TGF-b1 mRNA in the heart. mRNA levels were detected by real-time PCR and each bar represented the mean 6SD. **P,0.01, *P,0.05 vs. NC; ##P,0.01, #P,0.05 vs. MS. NC group (n = 10); MS group (n = 10); MS+A group (n = 11); MS+H group (n = 11). doi:10.1371/journal.pone.0067530.gHuan-Lian-Jie-Du-Tang for Cardiac Damages in RatsFigure 8. The activation of SOCS3, phospho-JNK, phospho- AKT and serine phospho- IRS1 in the heart. The left panels showed representative blots of the left ventricular. The right bar graph showed relative protein levels. Each bar represented the mean 6SD. **P,0.01, *P,0.05 vs. NC; ##P,0.01, #P,0.05 vs. MS. NC group (n = 10); MS group (n = 10); 16985061 MS+A group (n = 11); MS+H group (n = 11). doi:10.1371/journal.pone.0067530.gcytokine production and activation of inflammatory signaling pathways, is another mechanism [21]. In a chronic inflammatory response of MS, inflammatory cytokines such as TNF-a, IL-1 and IL-6 were activated [4]. In addition, in adipose tissue of obese rodents and humans, TNF-a expression is increased [22], and reducing TNF-a expression could reduce IR in obese rodents [23]. Inflammation-mediated IR implicates several pathways including IKKb/NF-kB, JNK and SOCS3, which are activated by inflammatory cytokines. Many studies demonstrated that inhibiting the activity of IKK, JNK and SOCS3 by pharmacological inhibition or gene knockout could improve IR [8,24?7,9]. In our study, the expression of inflammatory cytokines such as TNF-a, IL-1, and IL-6 was inhibited by pharmacological inhibitions, resulting in improving IR. Taken together, these results suggest that aberrant inflammation pathways may contribute to the onset of IR in MS rats. Insulin signaling pathway in metabolism is regulated by the insulin-stimulated tyrosine phosphorylation of IRS-1 and the activity of PI3-kinase/AKT signaling pathway. The PI3Kdependent activation of the AKT kinase is known to control programmed cell death and cellular metabolism [28]. Moreover, activated AKT could preserve cardiac function because in rodent models of myocardial infarction, bone marrow erived mesenchymal stem cells expressing constitutively activated AKT could enhance cardiomyocytes survival and organ function [29]. In our study, there were significant differences of left ventricle (LV) between the obese-fed and normal-fed rats, including LV structure (IVS and LVPW), diastolic function (A wave and E/A), and myocardial composition (the amount of collagen I/III). These differences were associated with reduced PI 3-kinase/AKT pathway. These results suggest that a long exposure to the obese-diet could inhibit insulin signaling, thereby inducing myocardial damage on both cardiac structure and function. The efficacy of aspirin (acetylsalicylic acid) on reducing serine phosphorylation of IRS-1 associated wit.
