Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity

Asnani, Aarti; Zheng, Baohui; Liu, Yan; Wang, You; Chen, Howard H.; Vohra, Anita; Chi, An; Cornella-Taracido, Ivan; Wang, Huijun; Johns, Douglas G.; Sosnovik, David E.; Peterson, Randall T.

doi:10.1172/jci.insight.96753

Cited by 37 publications

(35 citation statements)

References 35 publications

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“…In the current work, we observed a male-specific induction of Cyp1a1 gene expression 24 h after DOX administration. We previously reported that DOX upregulated CYP1A1 gene expression in H9c2 cardiomyoblasts [33] and in hearts of male Sprague Dawley rats [23], an observation that was later confirmed by other investigators [34,35]. Since inflammation has been shown to downregulate Cyp1a1 gene expression [16,36,37], the observed DOX-induced upregulation of the Cyp1a1 gene in the current work is likely mediated by mechanisms other than inflammation.…”

Section: Discussionsupporting

confidence: 82%

Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

Grant

Abdelgawad

Lewis

et al. 2020

IJMS

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Doxorubicin (DOX) is an effective chemotherapeutic agent used to treat a wide variety of malignancies. In addition to its multi-organ toxicity, DOX treatment has been shown to induce systemic inflammation in patients and experimental animals. Inflammation alters the expression of hepatic cytochrome P450 (CYP) enzymes, which play important roles in drug metabolism and DOX-induced toxicity. Significant sex differences have been reported in DOX-induced toxicity; however, sex differences in DOX-induced systemic inflammation and the potential effects on hepatic CYP expression have not been determined. In the current work, male and female C57Bl/6 mice were administered DOX (20 mg/kg by intraperitoneal injection), and groups of mice were sacrificed 24 and 72 h after DOX administration. DOX elicited a systemic inflammatory response in both male and female mice, but the inflammatory response was stronger in male mice. DOX altered the expression of hepatic CYP isoforms in a sex-dependent manner. Most notably, inhibition of Cyp2c29 and Cyp2e1 was stronger in male than in female mice, which paralleled the sex differences in systemic inflammation. Therefore, sex differences in DOX-induced systemic inflammation may lead to sexually dimorphic drug interactions, in addition to contributing to the previously reported sexual dimorphism in specific DOX-induced organ toxicity.

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Section: Discussionsupporting

confidence: 82%

Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

Grant

Abdelgawad

Lewis

et al. 2020

IJMS

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“…The zebrafish was selected as the in vivo model in this study due to its cardiac regenerative capacity, optical transparency during development, and genetically tractable system (4,6,7,9). We integrated 4D LSFM with a post-imaging synchronization algorithm (11,12) to acquire high-quality 3D volume rendering of the contracting heart.…”

Section: Discussionmentioning

confidence: 99%

“…While human induced pluripotent stem cells (hiPSCs) have been proposed to assess chemotherapy-induced cardiotoxicity (3), experimental models such as zebrafish (Danio rerio) heal by regenerating myocardium with highly conserved developmental genes (4), allowing for in vivo assessment of chemotherapy and cardiac function in an integrated organ system (5). In addition, zebrafish are increasingly utilized to model different types of heart failure and regeneration, for drug development, and to search for genetic modifiers (6)(7)(8)(9). However, their small heart size hinders precise functional and structural assessments, necessitating advanced light-sheet fluorescence microscopy (LSFM) with high spatiotemporal resolution for in vivo imaging of cardiac development, injury, and regeneration (10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Displacement analysis of myocardial mechanical deformation (DIAMOND) reveals segmental susceptibility to doxorubicin-induced injury and regeneration

Chen¹,

Ding²,

Chen³

et al. 2019

JCI Insight

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“…In isolated rat aortic rings, visnagin inhibited the vascular smooth muscle contraction induced by different agents [80]. Visnagin has also shown protective effects against doxorubicin cardiotoxicity mediated via cytochrome P450 family 1 (CYP1) inhibition [81] and modulation of mitochondrial malate dehydrogenase [82]. In addition, visnagin prevented the deposition of renal crystals in hyperoxaluric rats [83].…”

Section: Oxidative Medicine and Cellular Longevitymentioning

confidence: 99%

Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway

Hassanein

Sayed

Hussein

et al. 2020

Oxidative Medicine and Cellular Longevity

158

106

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The Keap1/Nrf2/ARE system is a central defensive mechanism against oxidative stress which plays a key role in the pathogenesis and progression of many diseases. Nrf2 is a redox-sensitive transcription factor controlling a variety of downstream antioxidant and cytodefensive genes. Nrf2 has a powerful anti-inflammatory activity mediated via modulating NF-κB. Therefore, pharmacological activation of Nrf2 is a promising therapeutic strategy for the treatment/prevention of several diseases that are underlined by both oxidative stress and inflammation. Coumarins are natural products with promising pharmacological activities, including antioxidant, anticancer, antimicrobial, and anti-inflammatory efficacies. Coumarins are found in many plants, fungi, and bacteria and have been widely used as complementary and alternative medicines. Some coumarins have shown an ability to activate Nrf2 signaling in different cells and animal models. The present review compiles the research findings of seventeen coumarin derivatives of plant origin (imperatorin, visnagin, urolithin B, urolithin A, scopoletin, esculin, esculetin, umbelliferone, fraxetin, fraxin, daphnetin, anomalin, wedelolactone, glycycoumarin, osthole, hydrangenol, and isoimperatorin) as antioxidant and anti-inflammatory agents, emphasizing the role of Nrf2 activation in their pharmacological activities. Additionally, molecular docking simulations were utilized to investigate the potential binding mode of these coumarins with Keap1 as a strategy to disrupt Keap1/Nrf2 protein-protein interaction and activate Nrf2 signaling.

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Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity

Cited by 37 publications

References 35 publications

Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

Displacement analysis of myocardial mechanical deformation (DIAMOND) reveals segmental susceptibility to doxorubicin-induced injury and regeneration

Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway

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