title: Xinmailong mitigated epirubicin-induced cardiotoxicity via inhibiting autophagy.
abstract: BACKGROUND
  Using insects, such as the cockroach, for the treatment of disease has a long history in traditional Chinese medicine. Xinmailong (XML) Injection, a bioactive composite extracted from Periplaneta americana (a species of cockroach), shows reasonable protective effects against cardiovascular injury and was approved for the use in the treatment of cardiac dysfunction in 2006, yet its cardio protective mechanisms remain unclear.
  
  
  OBJECTIVE
  The present study aims to examine the protective effects of XML against epirubicin-induced cardiotoxicity in vivo and determine its underlying mechanisms.
  
  
  METHODS
  The chemical characteristics of XML were identified using high performance liquid chromatography (HPLC). Rats were intraperitoneally injected with epirubicin and then treated with XML for 14 days. Survival rate, echocardiography, electrocardiographic recordings and Masson staining were used to evaluate the cardioprotective activity of XML. Western blot and quantitative real time reverse transcriptase polymerase chain reaction (RT-PCR) analyses were used to investigate the molecular mechanisms underlying the actions of XML.
  
  
  RESULTS
  XML treatment significantly enhanced the survival rate of rats from epirubicin-induced heart failure. XML prevented left ventricle dilatation, improved cardiac function. Furthermore, treatment with XML also significantly inhibited the accumulation of collagen, reduced the levels of mRNA for matrix metalloproteinases-9 (Mmp9) and transforming growth factor-β 1(Tgfb1). This action of XML therefore might be responsible, at least in part, for the attenuation of cardiac fibrotic remodeling. XML inhibited autophagy as evidenced by the decreased accumulation of Beclin1 and autophagy related 7 (Atg7), which are necessary to form autophagosome structures. Protein kinase B (PKB/Akt), phosphatidylinositol 3 kinase (PI3K) and B cell lymphoma2 (Bcl2) levels were up-regulated, while significantly decreased protein levels for phosphorylated P38 and extracellular regulated protein kinases 1/2 (Erk1/2) were observed in the XML treated rats. The autophagy related results suggested that the increase in PI3K/Akt levels and inhibition of the phosphorylation of P38 MAPK and Erk1/2 contributed to the anti-autophagic activity of XML.
  
  
  CONCLUSIONS
  Our data suggest that XML may be effective for mitigating epirubicin-induced cardiomyopathy and inhibits autophagy via activating the PI3K/Akt signaling pathway and inhibiting the Erk1/2 and P38 MAPK signaling pathways.
authors: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
authors: Hui
authors: H
authors: Li
authors: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
authors: Yiqing
authors: Y
authors: Mao
authors: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
authors: Qun
authors: Q
authors: Zhang
authors: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
authors: Qing
authors: Q
authors: Han
authors: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
authors: Zhenming
authors: Z
authors: Man
authors: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
authors: Jingyu
authors: J
authors: Zhang
authors: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
authors: Xi
authors: X
authors: Wang
authors: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
authors: Ruobi
authors: R
authors: Hu
authors: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
authors: Xuehui
authors: X
authors: Zhang
authors: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8. Electronic address: david.irwin@utoronto.ca.
authors: David M
authors: DM
authors: Irwin
authors: Beijing N&N Genetech Company Ltd., Beijing 100082, China. Electronic address: nngene@sohu.com.
authors: Gang
authors: G
authors: Niu
authors: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China. Electronic address: tanlab@bjmu.edu.cn.
authors: Huanran
authors: H
authors: Tan
mesh_terms: D000818:Animals; D001343:Autophagy; D002316:Cardiotonic Agents / Q000494:pharmacology*; D066126:Cardiotoxicity; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D015251:Epirubicin; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D002316:Cardiotonic Agents; D003094:Collagen; D004365:Drugs, Chinese Herbal; D015251:Epirubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C508962:Tgfb1 protein, rat; C000618382:xinmailong; C572337:Mmp9 protein, rat
keywords: Cardiotoxicity; Cardiovascular; Epirubicin; Periplaneta americana; Pharmacodynamics; Xinmailong