Protective effects of higenamine combined with [6]-gingerol against doxorubicin-induced mitochondrial dysfunction and toxicity in H9c2 cells and potential mechanisms

Wen, Jianxia; Wang, Jian; Li, Pengyan; Wang, Ruilin; Wang, Jiabo; Zhou, Xuelin; Zhang, Lu; Li, Haotian; Wei, Shizhang; Cai, Huadan; Yan, Zhao

doi:10.1016/j.biopha.2019.108881

Cited by 28 publications

(86 citation statements)

References 26 publications

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“…Therefore, a systematic study of drugs affecting RAAS may be of great significance for the treatment and prognosis of CHF. Previous studies have found that HG/[6]‐GR can promote mitochondrial energy metabolism and protects H9c2 cells from HF via up‐regulating the PPARα/PGC‐1α/Sirt3 pathways . However, the anti‐HF effect of HG/[6]‐GR has not been systematically studied in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…H9c2 cells were cultured in a CO 2 constant‐temperature incubator (37°C, saturated humidity atmosphere of 95% air and 5% CO 2 ). H9c2 rat cardiomyocyte cells were pre‐treated with 20 μmol/L HG, 20 μmol/L [6]‐GR or 20 μmol/L HG plus 20 μmol/L [6]‐GR following 5 μmol/L DOX for 24 hours as our previous study …”

Section: Methodsmentioning

confidence: 99%

“…Seahorse XFp Cell Energy Phenotype Test and Extracellular Flux (XFp) analyser (XFp, Seahorse Biosciences, MA) were performed according to the provided protocol. Cell processing was performed as our previous studies . After subsequent mixing and injection of the compounds (10 μmol/L oligomycin and 10 μmol/L carbonyl cyanide‐4‐(trifluoromethoxy) phenylhydrazone [FCCP]), the values of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), stressed OCR and stressed ECAR were determined in all wells three times.…”

Section: Methodsmentioning

confidence: 99%

“…RT‐PCR was performed on a QuantStudio™ Real‐Time PCR System version 1.3 (Applied Biosystems by Thermo Fisher Scientific). During the experiment, all the steps from sample extraction and storage to RNA extraction, testing the RNA samples, reverse transcription, primer design and validation and so on were strictly performed according to the operation prompt of Minimum Information for the Publication of Quantitative Real‐Time PCR Experiments (MIQE) . The related primer sequences are shown in Table .…”

Section: Methodsmentioning

confidence: 99%

“…The results indicated that the combined use of HG and [6]‐GR shows cardioprotective function against DOX‐induced cardiotoxicity via activating the PI3K/Akt signalling pathway . Moreover, our previous study has shown that HG combined with [6]‐GR (HG/[6]‐GR) can protect H9c2 cardiomyocyte from doxorubicin (DOX)‐induced cardiomyocyte toxicity, which alleviates cell mitochondrial respiratory impairment and energy metabolism disorder . HG and [6]‐GR may serve as the active components of Aconiti Lateralis Radix Praeparata (ALRP, Fuzi in Chinese) and Zingiberis Rhizoma (ZR, Ganjiang in Chinese), respectively.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic effects of higenamine combined with [6]‐gingerol on chronic heart failure induced by doxorubicin via ameliorating mitochondrial function

Wen

Zhang

Wang

et al. 2020

J Cellular Molecular Medi

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Higenamine (HG) is a natural benzylisoquinoline alkaloid isolated from Aconitum with positive inotropic and chronotropic effects. This study aimed to investigate the possible cardioprotective effects of HG combined with [6]-gingerol (HG/[6]-GR) against DOXinduced chronic heart failure (CHF) by comprehensive approaches. DOX-induced cardiotoxicity model in rats and H9c2 cells was established. Therapeutic effects of HG/[6]-GR on haemodynamics, serum indices and histopathology of cardiac tissue were analysed. Cell mitochondrial energy phenotype and cell mitochondrial fuel flex were measured by a Seahorse XFp analyser. Moreover, UHPLC-Q-TOF/MS was performed to explore the potential metabolites affecting the therapeutic effects and pathological process of CHF. To further investigate the potential mechanism of HG/[6]-GR, mRNA and protein expression levels of RAAS and LKB1/AMPK/Sirt1-related pathways were detected. The present data demonstrated that the therapeutic effects of HG/[6]-GR combination on CHF were presented in ameliorating heart function, down-regulation serum indices and alleviating histological damage of heart tissue. Besides, HG/[6]-GR has an effect on increasing cell viability of H9c2 cells, ameliorating DOX-induced mitochondrial dysfunction and elevating mitochondrial OCR and ECAR value. Metabolomics analyses showed that the therapeutic effect of HG/[6]-GR combination is mainly associated with the regulation of fatty acid metabolites and energy metabolism pathways. Furthermore, HG/ [6]-GR has an effect on down-regulating RAAS pathway-related molecules and up-regulating LKB1/AMPKα/Sirt1-related pathway. The present work demonstrates that HG/ [6]-GR prevented DOX-induced cardiotoxicity via the cardiotonic effect and promoting myocardial energy metabolism through the LKB1/AMPKα/Sirt1 signalling pathway, which promotes mitochondrial energy metabolism and protects against CHF. K E Y W O R D S [6]-gingerol, Aconiti Lateralis Radix Praeparata, chronic heart failure, doxorubicin, energy metabolism, higenamine | 4037 WEN Et al.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapeutic effects of higenamine combined with [6]‐gingerol on chronic heart failure induced by doxorubicin via ameliorating mitochondrial function

Wen

Zhang

Wang

et al. 2020

J Cellular Molecular Medi

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Promising effects of gingerol against toxins: A review article

et al. 2021

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Ginger is a medicinal and valuable culinary plant. Gingerols, as an active constituent in the fresh ginger rhizomes of Zingiber officinale, exhibit several promising pharmacological properties. This comprehensive literature review was performed to assess gingerol's protective and therapeutic efficacy against the various chemical, natural, and radiational stimuli. Another objective of this study was to investigate the mechanism of anti-inflammatory, antioxidant, and antiapoptotic properties of gingerol. It should be noted that the data were gathered from in vivo and in vitro experimental studies. Gingerols can exert their protective activity through different mechanisms and cell signaling pathways.For example, these are mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-kB), Wnt/β-catenin, nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), transforming growth factor beta1/Smad3 (TGF-β1/Smad3

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The modulation of SIRT1 and SIRT3 by natural compounds as a therapeutic target in doxorubicin‐induced cardiotoxicity: A review

Tabrizi

Yarmohammadi

Hayes

et al. 2021

J Biochem & Molecular Tox

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Doxorubicin (DOX) is a potent antitumor agent with a broad spectrum of activity; however, irreversible cardiotoxicity resulting from DOX treatment is a major issue that limits its therapeutic use. Sirtuins (SIRTs) play an essential role in several physiological and pathological processes including oxidative stress, apoptosis, and inflammation. It has been reported that SIRT1 and SIRT3 can act as a protective molecular against DOX-induced myocardial injury through targeting numerous signaling pathways. Several natural compounds (NCs), such as resveratrol, sesamin, and berberine, with antioxidative, anti-inflammation, and antiapoptotic effects were evaluated for their potential to suppress the cardiotoxicity induced by DOX via targeting SIRT1 and SIRT3. Numerous NCs exerted their therapeutic effects on DOX-mediated cardiac damage via targeting different signaling pathways, including SIRT1/LKB1/AMPK, SIRT1/PGC-1α, SIRT1/NLRP3, and SIRT3/FoxO. SIRT3 also ameliorates cardiotoxicity by enhancing mitochondrial fusion.

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Protective effects of higenamine combined with [6]-gingerol against doxorubicin-induced mitochondrial dysfunction and toxicity in H9c2 cells and potential mechanisms

Cited by 28 publications

References 26 publications

Therapeutic effects of higenamine combined with [6]‐gingerol on chronic heart failure induced by doxorubicin via ameliorating mitochondrial function

Therapeutic effects of higenamine combined with [6]‐gingerol on chronic heart failure induced by doxorubicin via ameliorating mitochondrial function

Promising effects of gingerol against toxins: A review article

The modulation of SIRT1 and SIRT3 by natural compounds as a therapeutic target in doxorubicin‐induced cardiotoxicity: A review

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