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Diethyl Blechnic, a Novel Natural Product Isolated from Salvia miltiorrhiza Bunge, Inhibits Doxorubicin-Induced Apoptosis by Inhibiting ROS and Activating JNK1/2.

ABSTRACT: Doxorubicin (DOX) is a widely used antineoplastic agent in clinics. However, its clinical application is largely limited by its cardiotoxicity. Diethyl blechnic (DB) is a novel compound isolated from Salvia miltiorrhiza Bunge. Here, we study the effect of DB on DOX-induced cardiotoxicity and its underlying mechanisms. Cellular viability was tested by 3-[-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and protein level was evaluated by Western blotting. 5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining was performed to determine the mitochondrial membrane potential (MMP). Hoechst 33342 staining and TUNEL staining was performed to test the apoptosis. Reactive oxygen species (ROS) generation was investigated by using flow cytometry. DB significantly inhibited DOX-induced apoptosis in H9c2 cells and primary cultured cardiomyocytes. Moreover, DB decreased cell apoptotic morphological changes and reversed the mitochondrial membrane potential induced by DOX. Meanwhile, pre-treatment with DB increased the expression levels of B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xl), and survivin and reduced the expression levels of Bcl-2-associated X protein (Bax), p-p53, cytochrome c (cyt c), and cleaved-caspase 3, 7, 8, 9 in the protein levels in DOX-treated H9c2 cells. Furthermore, DB suppressed ROS generation. The DB-mediated protective effects were accompanied by increased c-Jun N-terminal kinase1/2 (JNK1/2) expression. In addition, SP600125, the inhibitor of JNK1/2, abolished the protective effect of DB. We concluded that DB protected cardiomyocytes against DOX-induced cytotoxicity by inhibiting ROS and activating the JNK1/2 pathway. Therefore, DB is a promising candidate as a cardioprotective agent against DOX-induced cardiotoxicity.

SUBMITTER: Yu J

PROVIDER: S-EPMC6032151 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Diethyl Blechnic, a Novel Natural Product Isolated from <i>Salvia miltiorrhiza</i> Bunge, Inhibits Doxorubicin-Induced Apoptosis by Inhibiting ROS and Activating JNK1/2.

Yu Jie J Gao Hongwei H Wu Chuanhong C Xu Qiong-Ming QM Lu Jin-Jian JJ Chen Xiuping X

International journal of molecular sciences 20180619 6

Doxorubicin (DOX) is a widely used antineoplastic agent in clinics. However, its clinical application is largely limited by its cardiotoxicity. Diethyl blechnic (DB) is a novel compound isolated from <i>Salvia miltiorrhiza</i> Bunge. Here, we study the effect of DB on DOX-induced cardiotoxicity and its underlying mechanisms. Cellular viability was tested by 3-[-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and protein level was evaluated by Western blotting. 5,5’,6,6’-tetrachlo ...[more]

PMID: 29921821

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Project description:Background: Hypertension is a major risk factor for cardiovascular diseases and the leading cause of mortality worldwide. Despite the availability of antihypertensive drugs, alternative treatments are needed due to the adverse events associated with their use. Previous studies have shown that SABP, a combination of aqueous active metabolites of Salvia Miltiorrhiza Bunge DSS, Sal-A, Sal-B and PAL, has a significant antihypertensive effect. However, the underlying mechanisms remain unknown. Objective: This study aimed to determine the effects of SABP on vascular inflammation, oxidative stress, and vascular remodeling in spontaneously hypertensive rats (SHRs). Additionally, the response of adventitial fibroblasts in SHRs to SABP treatment was also studied, including their proliferation, differentiation, and migration. Methods: SABP or perindopril (positive control) were administered intraperitoneally to SHRs, and systolic blood pressure was measured using a tail-cuff approach. The effects of SABP on oxidative stress, inflammation, and vascular remodeling were investigated by transmission electron microscopy, histochemical staining, and Western blot. Adventitial fibroblasts were isolated and cultured from the adventitia of thoracic aorta in SHR and WKY rats. CCK8 assay, wound healing method and immunostaining were used to observe the effect of SABP on fibroblasts proliferation, migration and transformation into myofibroblasts. Moreover, Western blot analysis was also performed to detect the proteins related to oxidative stress, inflammation and fibrosis in adventitial fibroblasts. Results: SHRs displayed higher blood pressure with significant vascular remodeling compared to WKY rats. The thoracic aorta and adventitial fibroblasts of SHRs exhibited significant oxidative stress, inflammation and fibrosis. SABP treatment repressed oxidative stress, inflammatory reaction and vascular remodeling of thoracic aorta in SHR through the ROS/TLR4/NF-κB signaling pathway, and inhibited fibrosis of thoracic aorta. Additionally, SABP inhibited the proliferation and migration of adventitial fibroblasts and their transformation to myofibroblasts in vitro through the TGFβ/Smad3 signaling pathway. Conclusion: These findings suggest that SABP have potential as an alternative treatment for hypertension by ameliorating oxidative stress, inflammation and fibrosis. Further research is needed to fully understand the mechanisms underlying the effects of SABP.

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Dataset Information

Diethyl Blechnic, a Novel Natural Product Isolated from Salvia miltiorrhiza Bunge, Inhibits Doxorubicin-Induced Apoptosis by Inhibiting ROS and Activating JNK1/2.

Publications

Diethyl Blechnic, a Novel Natural Product Isolated from <i>Salvia miltiorrhiza</i> Bunge, Inhibits Doxorubicin-Induced Apoptosis by Inhibiting ROS and Activating JNK1/2.

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