Withaferin A Prevents Myocardial Ischemia/Reperfusion Injury by Upregulating AMP-Activated Protein Kinase-Dependent B-Cell Lymphoma2 Signaling

Guo, Rui; Gan, Lu; Yan, Zheyi; Xie, Dina; Gao, Erhe; Christopher, Theodore A.; Lopez, Bernard L.; Ma, Xin‐Liang; Wang, Yajing

doi:10.1253/circj.cj-18-1391

Cited by 21 publications

(14 citation statements)

References 41 publications

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“…Many studies have demonstrated effect of WFA on apoptosis of cardiomyocytes [ 63 ]. Our previous work have shown that WFA attenuated skeletal muscle cachexia [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Withaferin A attenuates ovarian cancer-induced cardiac cachexia

2020

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Cachexia is a common multifactorial syndrome in the advanced stages of cancer and accounts for approximately 20–30% of all cancer-related fatalities. In addition to the progressive loss of skeletal muscle mass, cancer results in impairments in cardiac function. We recently demonstrated that WFA attenuates the cachectic skeletal muscle phenotype induced by ovarian cancer. The purpose of this study was to investigate whether ovarian cancer induces cardiac cachexia, the possible pathway involved, and whether WFA attenuates cardiac cachexia. Xenografting of ovarian cancer induced cardiac cachexia, leading to the loss of normal heart functions. Treatment with WFA rescued the heart weight. Further, ovarian cancer induced systolic dysfunction and diastolic dysfunction Treatment with WFA preserved systolic function in tumor-bearing mice, but diastolic dysfunction was partially improved. In addition, WFA abrogated the ovarian cancer-induced reduction in cardiomyocyte cross-sectional area. Finally, treatment with WFA ameliorated fibrotic deposition in the hearts of tumor-bearing animals. We observed a tumor-induced MHC isoform switching from the adult MHCα to the embryonic MHCβ isoform, which was prevented by WFA treatment. Circulating Ang II level was increased significantly in the tumor-bearing, which was lowered by WFA treatment. Our results clearly demonstrated the induction of cardiac cachexia in response to ovarian tumors in female NSG mice. Further, we observed induction of proinflammatory markers through the AT 1 R pathway, which was ameliorated by WFA, in addition to amelioration of the cachectic phenotype, suggesting WFA as a potential therapeutic agent for cardiac cachexia in oncological paradigms.

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“…Many studies have demonstrated effect of WFA on apoptosis of cardiomyocytes [ 63 ]. Our previous work have shown that WFA attenuated skeletal muscle cachexia [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Withaferin A attenuates ovarian cancer-induced cardiac cachexia

2020

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“…Withaferin A also acts on cellular pathways, such as cell cycle arrest [ 296 , 297 ], inhibits apoptosis via activated Akt-mediated inhibition of oxidative stress and ROS-dependent mitochondrial dysfunction in human colorectal cancer cells [ 298 , 299 ], and inhibits endoplasmic reticulum stress-associated apoptosis [ 300 ]. Low doses of withaferin A are cardioprotective in ischemia/reperfusion events via upregulation of the antiapoptotic mitochondrial pathway in an AMPK-dependent manner [ 301 ]. Another group of recently-synthetized inhibitors of TASK-3 channel activity is the 5,6,7,8-tetrahydropyrido [4,3-d]pyrimidine (THPP)-derived compounds IN-THPP and mitoIN-THPP, which differs by the addition of a triphenylphosphonium (TPP) group [ 294 ].…”

Section: Modulators Of Mitochondrial Task Channelsmentioning

confidence: 99%

Alternative Targets for Modulators of Mitochondrial Potassium Channels

et al. 2022

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Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.

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“…In cancer cells, where the basal ROS levels are already relatively high, WA is able to further increase oxidative stress and promote cell death [ 90 , 91 ]. This is in stark contrast with the chronic inflammatory disease setting, where WA attenuates oxidative stress and suppresses ROS production, thereby decreasing disease severity [ 56 , 60 , 92 , 93 ]. This suppression is often mediated by activation of the anti-inflammatory Nrf2 pathway, which inhibits several inflammatory mediators and enzymes and activates antioxidant target genes [ 94 ].…”

Section: Molecular Targets Of Withaferin a In The Inflammatory Resmentioning

confidence: 99%

Tackling Chronic Inflammation with Withanolide Phytochemicals—A Withaferin A Perspective

Logie

Berghe

2020

Antioxidants

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Chronic inflammatory diseases are considered to be one of the biggest threats to human health. Most prescribed pharmaceutical drugs aiming to treat these diseases are characterized by side-effects and negatively affect therapy adherence. Finding alternative treatment strategies to tackle chronic inflammation has therefore been gaining interest over the last few decades. In this context, Withaferin A (WA), a natural bioactive compound isolated from Withania somnifera, has been identified as a promising anti-cancer and anti-inflammatory compound. Although the majority of studies focus on the molecular mechanisms of WA in cancer models, recent evidence demonstrates that WA also holds promise as a new phytotherapeutic agent against chronic inflammatory diseases. By targeting crucial inflammatory pathways, including nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2 related factor 2 (Nrf2) signaling, WA suppresses the inflammatory disease state in several in vitro and preclinical in vivo models of diabetes, obesity, neurodegenerative disorders, cystic fibrosis and osteoarthritis. This review provides a concise overview of the molecular mechanisms by which WA orchestrates its anti-inflammatory effects to restore immune homeostasis.

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Withaferin A Prevents Myocardial Ischemia/Reperfusion Injury by Upregulating AMP-Activated Protein Kinase-Dependent B-Cell Lymphoma2 Signaling

Cited by 21 publications

References 41 publications

Withaferin A attenuates ovarian cancer-induced cardiac cachexia

Withaferin A attenuates ovarian cancer-induced cardiac cachexia

Alternative Targets for Modulators of Mitochondrial Potassium Channels

Tackling Chronic Inflammation with Withanolide Phytochemicals—A Withaferin A Perspective

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