Vitamin D<sub>3</sub>attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission

Liu, Xingyao; Wang, Shuang; Jin, Shengzi; Huang, Siqi; Liu, Yun

doi:10.1039/d2fo01028c

Cited by 17 publications

(9 citation statements)

References 53 publications

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“…Previously, VD/VDR has been demonstrated to avert ferroptosis in hippocampal neuron via activating the Nrf2/HO-1 signaling [29] . Additionally, VD has been shown to inhibit ferroptosis in liver, kidney, intestine, and hypoxic-ischemic brain tissues through various pathways [30][31][32][33] , which is consistent with our observations. We found in vivo that vitamin D alleviates myocardial injury, likely by downregulating NRG1 expression and inhibiting Erbb4 activation.…”

Section: Discussionsupporting

confidence: 92%

Vitamin D attenuates diabetic myocardial injury via the Erbb4/ferroptosis axis

Song,

Miao,

Zhang

et al. 2023

Preprint

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BackgroundHyperglycemia and hyperlipidemia lead to the ferroptosis, well as the phosphorylation of Erbb4, and thereby increase the risk of cardiac hypertrophy. Thus, our investigation aims to explore whether vitamin D could mitigate diabetic cardiac injury through modulation of the Erbb4/ferroptosis axis.Methods and resultsKKAy mice fed on a high-fat diet were utilized to construct the prediabetic model, which showed an up-regulated phosphorylation of Erbb4, with concurrent ferroptosis in cardiac tissues. Following the intervention with vitamin D for 16 weeks, the activity of Erbb4/YAP signaling was suppressed and the severeness of ferroptosis was improved. Meanwhile disturbances in glucose-lipid metabolism and insulin secretion induced by high fat were alleviated, along with improvements in cardiac hypertrophy and myocardial function. Moreover, we established anin vitrodamage model by introducing H9c2 myocardial cells to high glucose (HG, 33.3 mM) and palmitic acid (PA, 0.25 mM). Unsurprisingly, similar results have been acquired after vitamin D supplementation. Subsequently, selective inhibitors of Erbb4 (Dacomitinib) and ferroptosis (Ferrostatin-1) were applied to evaluate the efficiency of Erbb4 signaling on modulating ferroptosisin vitro, and conclusively confirming that inhibiting of Erbb4 indeed reduce ferroptosis under HG and PA stimulus. Additionally, treatment of vitamin D was found to reduce cardiomyocyte hypertrophy and prevent cell death by inhibiting Erbb4 activity. Interestingly, the combined intervention of Vitamin D and Dacomitinib exerted a synergistic effect on ameliorating the abnormal conditions.ConclusionsOur study unveils, the correlation between Erbb4 and ferroptosis in diabetic heart. Providing evidences that vitamin D supplementation can improve ferroptosis related diabetic cardiac injury through inactivation of Erbb4. Proposing that the combination treatment of vitamin D and Erbb4 inhibitors may emerge as a highly feasible clinical strategy for diabetic myocardial injury.

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Section: Discussionsupporting

confidence: 92%

Vitamin D attenuates diabetic myocardial injury via the Erbb4/ferroptosis axis

Song,

Miao,

Zhang

et al. 2023

Preprint

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“…Liu et al showed that vitamin D alleviated cisplatin-induced intestinal injury in a 7-week-old male mice by inhibiting chemotherapy-induced ferroptosis, a recently discovered mechanism of cisplatin antineoplastic activity. It is likely that cisplatin also induces intestinal damage by this alternative form of programmed cell death, involving failure of the glutathione-dependent antioxidant defences, which results in unchecked lipid peroxidation and cell death [48]. Similar to previous studies, this study showed that vitamin D could reduce proinflammatory cytokines and regulate tight junction protein expression, preventing intestinal injury [48].…”

Section: Tight Junction Barrier Regulationsupporting

confidence: 85%

“…It is likely that cisplatin also induces intestinal damage by this alternative form of programmed cell death, involving failure of the glutathione-dependent antioxidant defences, which results in unchecked lipid peroxidation and cell death [48]. Similar to previous studies, this study showed that vitamin D could reduce proinflammatory cytokines and regulate tight junction protein expression, preventing intestinal injury [48].…”

Section: Tight Junction Barrier Regulationsupporting

confidence: 85%

Vitamin D is a potential treatment for the management of gastrointestinal mucositis

Munem,

Thianhlun,

Anderson

et al. 2023

Current Opinion in Supportive &Amp; Palliative Care

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Purpose of the review Gastrointestinal mucositis (GM) is a severe side effect of cancer treatments, negatively impacting the patient’s quality of life, and has limited treatment. GM consists of complex biological processes involving apoptosis and inflammation, leading to damage and ulceration of the gastrointestinal system. Recently, vitamin D has been shown to have multiple roles in the gut, including immunomodulation, epithelial barrier regulation and microbiome regulation. Hence, this review aims to put forth vitamin D as a potential therapeutic due to its protective role in the intestine. Recent findings Recent studies have shown that vitamin D can reduce intestinal inflammation by reducing NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation. Vitamin D also targets and maintains the intestinal epithelial barrier via the tight junction protein expression and the inhibition of microbiome translocation. Significant evidence also suggests that vitamin D exerts multiple therapeutic effects through binding to vitamin D receptors (VDRs), and the downregulation of VDR has been associated with the severity of the disease. Additionally, vitamin D deficiency is reported in cancer patients. Summary There is a dire need for effective treatment for GM, and recent animal and human studies show that vitamin D may be a potential therapy to prevent or treat GM.

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“…However, when used at their nonlethal concentrations, all these lipids potently inhibited cell death triggered by the ferroptosis inducers, including IKE and RSL3 (Figure , Table S2). While the antiferroptotic properties of 7-DHC, vitamin D 3 , and the precursor of vitamin A, β-carotene, were previously demonstrated, − to our knowledge, this is the first study that reports the inhibition of ferroptosis by the two forms of vitamin A including retinol and retinal. Previously, vitamin A was reported to function as either a pro-oxidant or an antioxidant, depending on oxygen tension in the tissues or organs. − Here, vitamin A appeared to function as an antioxidant and a ferroptosis inhibitor.…”

Section: Discussionmentioning

confidence: 71%

Differential Contributions of Distinct Free Radical Peroxidation Mechanisms to the Induction of Ferroptosis

Zhang

Hooper

et al. 2023

JACS Au

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Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Lipid peroxidation can propagate through either the hydrogen-atom transfer (HAT) or peroxyl radical addition (PRA) mechanism. However, the contribution of the PRA mechanism to the induction of ferroptosis has not been studied. In this study, we aim to elucidate the relationship between the reactivity and mechanisms of lipid peroxidation and ferroptosis induction. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D 3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we found that conjugated PUFAs, including conjugated linolenic acid (CLA 18:3) and conjugated linoleic acid (CLA 18:2), can induce or potentiate ferroptosis much more potently than nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. The different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.

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Vitamin D₃attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission

Abstract: Intestinal injury is one of the main side-effects of cisplatin (CP) chemotherapy, severely limiting the clinical application of cisplatin. Vitamin D3 is an essential nutrient for mammals and exists in...

Cited by 17 publications

References 53 publications

Vitamin D attenuates diabetic myocardial injury via the Erbb4/ferroptosis axis

Vitamin D attenuates diabetic myocardial injury via the Erbb4/ferroptosis axis

Vitamin D is a potential treatment for the management of gastrointestinal mucositis

Differential Contributions of Distinct Free Radical Peroxidation Mechanisms to the Induction of Ferroptosis

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Vitamin D3attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission

Abstract: Intestinal injury is one of the main side-effects of cisplatin (CP) chemotherapy, severely limiting the clinical application of cisplatin. Vitamin D3 is an essential nutrient for mammals and exists in...

Cited by 17 publications

References 53 publications

Vitamin D attenuates diabetic myocardial injury via the Erbb4/ferroptosis axis

Vitamin D attenuates diabetic myocardial injury via the Erbb4/ferroptosis axis

Vitamin D is a potential treatment for the management of gastrointestinal mucositis

Differential Contributions of Distinct Free Radical Peroxidation Mechanisms to the Induction of Ferroptosis

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Product

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Vitamin D₃attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission