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Functional Redox Proteomics Reveal That Salvia miltiorrhiza Aqueous Extract Alleviates Adriamycin-Induced Cardiomyopathy via Inhibiting ROS-Dependent Apoptosis.

ABSTRACT: The anticancer agent adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity, while Salvia miltiorrhiza (SM) is a Chinese herb widely used for the treatment of cardiovascular disorders and its aqueous extract (SMAE) has shown anticancer as well as antioxidant effects. In the current study, we aimed at investigating the synergistic effect and potent molecular mechanisms of SMAE with a focus on the cardioprotective benefit observed under ADR adoption. Histopathological analysis indicated that SMAE could substantially alleviate cardiomyopathy and cell apoptosis caused by ADR. Meanwhile, the two-dimensional electrophoresis (2-DE) oxyblots demonstrated that SMAE treatment could effectively reduce carbonylation of specific proteins associated with oxidative stress response and various metabolic pathways in the presence of ADR. SMAE application also showed protective efficacy against ADR-mediated H9c2 cell death in a dose-dependent manner without causing any cytotoxicity and significantly attenuated the reactive oxygen species production. Particularly, the simultaneous administration of ADR and SMAE could remarkably suppress the growth of breast cancer cells. We also noticed that there was a marked upregulation of detoxifying enzyme system in the presence of SMAE, and its exposure also contributed to an increase in Nrf2 and HO-1 content as well. SMAE also amended the ERK/p53/Bcl-xL/caspase-3 signaling pathways and the mitochondrial dysfunction, which eventually attribute to apoptotic cathepsin B/AIF cascades. Correspondingly, both the ERK1/2 inhibitor (U0126) and pan-caspase inhibitor (Z-VAD-FMK) could at least partially abolish the ADR-associated cytotoxicity in H9c2 cells. Collectively, these results support that ROS apoptosis-inducing molecule release is closely involved in ADR-induced cardiotoxicity while SMAE could prevent or mitigate the causative cardiomyopathy through controlling multiple targets without compromising the efficacy of chemotherapy.

SUBMITTER: Hung YC

PROVIDER: S-EPMC7501560 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Functional Redox Proteomics Reveal That <i>Salvia miltiorrhiza</i> Aqueous Extract Alleviates Adriamycin-Induced Cardiomyopathy via Inhibiting ROS-Dependent Apoptosis.

Hung Yu-Chiang YC Wang Pei-Wen PW Lin Tung-Yi TY Yang Pei-Ming PM You Jyh-Sheng JS Pan Tai-Long TL

Oxidative medicine and cellular longevity 20200909

The anticancer agent adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity, while <i>Salvia miltiorrhiza</i> (SM) is a Chinese herb widely used for the treatment of cardiovascular disorders and its aqueous extract (SMAE) has shown anticancer as well as antioxidant effects. In the current study, we aimed at investigating the synergistic effect and potent molecular mechanisms of SMAE with a focus on the cardioprotective benefit observed under ADR adoption. Histopatholo ...[more]

PMID: 32963697

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Project description:Lung adenocarcinoma is the most common subtype of non-small cell lung carcinoma. Tanshinone I is an important fat-soluble component in the extract of Salvia miltiorrhiza that has been reported to inhibit lung adenocarcinoma cell proliferation. However, no studies have clearly demonstrated changes in lung adenocarcinoma gene expression and signaling pathway enrichment following Tanshinone I treatment. And it remains unclear whether salvianolate has an effect on lung adenocarcinoma. The present study downloaded the GSE9315 dataset from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) and the underlying signaling pathways involved after Tanshinone I administration in the lung adenocarcinoma cell line CL1-5. The results revealed that there were 28 and 102 DEGs in the low dosage group (0.01 and 0.10 µg/ml Tanshinone I) and medium dosage groups (1 and 10 µg/ml Tanshinone I), respectively. In the low dosage group, DEGs were mainly enriched in 'positive regulation of T-helper cell differentiation' and 'protein complex'. In the medium dosage group, 102 DEGs were enriched in 'MAPK cascade' and 'extracellular exosome'. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated enrichment of both groups in the PI3K-Akt signaling pathway. Furthermore, there were nine overlapping DEGs [ADP ribosylation factor-interacting protein 2, chemokine (C-X-C motif) ligand 6, SH2 domain-containing adaptor protein B, Src homology 2 domain-containing transforming protein1, collagen type VI α1 chain, elastin, integrin subunit α, endoplasmic reticulum mannosyl-oligosaccharide 1,2-α-mannosidase and sterile α motif domain-containing 9 like] between the two groups, which serve to be potential targets for the treatment of lung adenocarcinoma. The present study also investigated the possible effects of salvianolate on lung adenocarcinoma in vivo using nude mouse xenograft models injected with the A549 cell line. The data revealed that salvianolate not only suppressed lung adenocarcinoma tumor growth of in nude mice, but also downregulated the expression levels of ATP7A and ATP7B, which are important proteins in the tumorigenesis and chemotherapy of lung adenocarcinoma. The present study provided evidence for the potential use of Salvia miltiorrhiza extract for treating lung adenocarcinomas in the clinic.

Project description:AimTo investigate the hepatoprotective effects and mechanisms of an extract of Salvia miltiorrhiza and Carthamus tinctorius in vivo.MethodsC57BL/6J mice were randomly assigned to five groups and intraperitoneally administered 0.9% saline, Salvia miltiorrhiza and Carthamus tinctorius extract [Danhong injection (DHI), 0.75 and 3 g/kg mixed extract] or reduced glutathione for injection (RGI, 300 mg/kg) for 30 min before exposure to lipopolysaccharide (LPS, 16 mg/kg). After intraperitoneal LPS stimulation for 90 min or 6 h, the mice were sacrificed by ether anaesthesia, and serum and liver samples were collected. Histological analysis (H&E) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining were performed. Alanine transferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), glutathione-S-transferase (GST), malondialdehyde (MDA), tumour necrosis factor (TNF)-α, interleukin (IL)-6, and caspase-3 levels were measured. Bax, Bcl-2, P-IκBα, IκBα, P-NF-κB p65, and NF-κB p65 protein levels were determined by Western blot. TNF-α, IL-6, caspase-3, Bax and Bcl-2 mRNA expression was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR).ResultsHematoxylin-eosin staining and TUNEL results suggested that DHI (3 g/kg) treatment alleviated inflammatory and apoptotic (P < 0.01) injury in the liver of mice. DHI treatment dose-dependently blunted the abnormal changes in biochemical parameters such as ALT (72.53 ± 2.83 for 3 g/kg, P < 0.01), AST (76.97 ± 5.00 for 3 g/kg, P < 0.01), TBil (1.17 ± 0.10 for 3 g/kg, P < 0.01), MDA (0.81 ± 0.36 for 3 g/kg, P < 0.01), and GST (358.86 ± 12.09 for 3 g/kg, P < 0.01). Moreover, DHI (3 g/kg) remarkably decreased LPS-induced protein expression of TNF-α (340.55 ± 10.18 for 3 g/kg, P < 0.01), IL-6 (261.34 ± 10.18 for 3 g/kg, P < 0.01), and enzyme activity of caspase-3 (0.93 ± 0.029 for 3 g/kg, P < 0.01). The LPS-induced mRNA expression of TNF-α, IL-6 and caspase-3 was also decreased by DHI. Western blot analysis revealed that DHI antagonised LPS-stimulated decrease of Bcl-2 and increase of Bax protein expression. Furthermore, DHI inhibited LPS-induced IκBα and NF-κB p65 phosphorylation.ConclusionDHI may be a multi-function protectant against acute hepatic injury in mice through its anti-inflammatory, anti-oxidative and anti-apoptotic activities.

Dataset Information

Functional Redox Proteomics Reveal That Salvia miltiorrhiza Aqueous Extract Alleviates Adriamycin-Induced Cardiomyopathy via Inhibiting ROS-Dependent Apoptosis.

Publications

Functional Redox Proteomics Reveal That <i>Salvia miltiorrhiza</i> Aqueous Extract Alleviates Adriamycin-Induced Cardiomyopathy via Inhibiting ROS-Dependent Apoptosis.

Similar Datasets

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