Hesperidin protects against cisplatin-induced cardiotoxicity in mice by regulating the p62–Keap1–Nrf2 pathway

Jia, Yongyi; Guo, Hui; Cheng, Xizhen; Zhang, Yuling; Si, Mingdong; Shi, Jing; Ma, Donglai

doi:10.1039/d2fo00298a

Cited by 12 publications

(7 citation statements)

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“…Nrf2 functions as a central regulator of downstream antioxidant enzymes, playing a significant role in the activation of SOD and CAT, and the Nrf2 signaling pathway plays a vital role in cellular defense against oxidative stress. [31][32][33] Keap1 is the most important negative regulator of Nrf2, binding with Nrf2 and promoting its degradation under no-stress conditions. 34 P62 (also known as SQSTM1) is a multifunctional stress-induced protein involved in selective autophagy and is crucial for the activation of the Nrf2 signalling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Under normal conditions, Keap1 binds to Nrf2, leading to its degradation by the ubiquitin-proteasome system. 33 However, when cells encounter oxidative stress, p62 acts as an adaptor protein and interacts with both Keap1 and Nrf2. Upon stress, p62 sequesters Keap1, preventing it from targeting Nrf2 for degradation.…”

Section: Discussionmentioning

confidence: 99%

“…The data showed that TA decreased the Keap1 gene expression and increased the levels of p62 and Nrf2 genes. Nrf2 functions as a central regulator of downstream antioxidant enzymes, playing a significant role in the activation of SOD and CAT , and the Nrf2 signaling pathway plays a vital role in cellular defense against oxidative stress 31‐33 . Keap1 is the most important negative regulator of Nrf2 , binding with Nrf2 and promoting its degradation under no‐stress conditions 34 .…”

Section: Discussionmentioning

confidence: 99%

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Tannic acid alleviates ETEC K88‐induced intestinal damage through regulating the p62‐keap1‐Nrf2 and TLR4‐NF‐κB‐NLRP3 pathway in IPEC‐J2 cells

Liu,

Guo

2024

J Sci Food Agric

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BackgroundTannic acid (TA), a naturally occurring polyphenol, has shown diverse potential in preventing intestinal damage in piglet diarrhea induced by ETEC K88. However, the protective effect of TA on ETEC k88 infection‐induced post‐weaning diarrhea and its potential mechanism has not been well elucidated. Therefore, an animal trial was carried out to investigate the effects of dietary supplementation with TA on the intestinal diarrhea of weaned piglets challenged with ETEC K88. In addition, porcine intestinal epithelial cells were used as an in vitro model to explore the mechanism through which TA alleviates intestinal oxidative damage and inflammation.ResultsThe results indicated that TA supplementation (2 g·kg‐1 and 4 g·kg‐1) reduced diarrhea rate, enzyme activity (DAO and MAD) and serum inflammatory cytokines concentration (TNF‐α, IL‐1β) (P < 0.05) compared to the IG group in vivo. In vitro, TA treatment effectively alleviated ETEC‐induced cytotoxicity, increased the expression of ZO‐1, occludin and claudin‐1 at both mRNA and protein levels. Moreover, TA pre‐treatment increased the activity of antioxidant enzymes (such as T‐SOD) and decreased serum cytokine levels (TNF‐α, IL‐1β). Furthermore, TA increased cellular antioxidant capacity by activating the Nrf2 signaling pathway and decreased inflammatory response by down‐regulating the expression of TLR4, MyD88, NF‐kB and NLRP3.ConclusionThe study showed that TA reduced the diarrhea rate of weaned piglets by restoring the intestinal mucosal mechanical barrier function, alleviating oxidative stress and inflammation. The underlying mechanismwas achieved by modulating p62‐keap1‐Nrf2 and TLR4‐NF‐κB‐NLRP3 pathway.This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Tannic acid alleviates ETEC K88‐induced intestinal damage through regulating the p62‐keap1‐Nrf2 and TLR4‐NF‐κB‐NLRP3 pathway in IPEC‐J2 cells

Liu,

Guo

2024

J Sci Food Agric

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“…p62 is also an important autophagy marker, which can indicate protein accumulation and degradation. By interacting with Keap1/Nrf2, which plays an important role in regulating oxidative stress, while p62 is participated in cell survival, growth and death in cardiovascular diseases ( 150 , 151 ). At present, p62/Keap1/Nrf2 targeting system and its related pathways (such as autophagy) are potential strategies for the treatment of cardiovascular diseases.…”

Section: Role Of Cascade Autophagy In Cardiovascular Disease Through ...mentioning

confidence: 99%

The role of autophagy in cardiovascular disease: Cross-interference of signaling pathways and underlying therapeutic targets

Jiang

Zhou

Yang

et al. 2023

Front. Cardiovasc. Med.

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Autophagy is a conserved lysosomal pathway for the degradation of cytoplasmic proteins and organelles, which realizes the metabolic needs of cells and the renewal of organelles. Autophagy-related genes (ATGs) are the main molecular mechanisms controlling autophagy, and their functions can coordinate the whole autophagic process. Autophagy can also play a role in cardiovascular disease through several key signaling pathways, including PI3K/Akt/mTOR, IGF/EGF, AMPK/mTOR, MAPKs, p53, Nrf2/p62, Wnt/β-catenin and NF-κB pathways. In this paper, we reviewed the signaling pathway of cross-interference between autophagy and cardiovascular diseases, and analyzed the development status of novel cardiovascular disease treatment by targeting the core molecular mechanism of autophagy as well as the critical signaling pathway. Induction or inhibition of autophagy through molecular mechanisms and signaling pathways can provide therapeutic benefits for patients. Meanwhile, we hope to provide a unique insight into cardiovascular treatment strategies by understanding the molecular mechanism and signaling pathway of crosstalk between autophagy and cardiovascular diseases.

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“…Despite this, its clinical use is often limited due to the related side effects including cardiotoxicity and neuropathy [ 182 ]. In a very recent publication that was carried out by Jia et al, the cardioprotection exerted by hesperidin, an abundant and economical dietary bioflavonoid, against cisplatin-induced cardiotoxicity in mice was attributed to the regulation of the p62 (rescue)/Keap1 (down-regulation)/Nrf2 (rescue) pathway, leading to the inhibition of oxidative stress, inflammation, and apoptosis [ 183 ].…”

Section: Nrf2 Pathway Modulation and Its Connection With Cardiotoxici...mentioning

confidence: 99%

The Therapeutic Potential of Carnosine as an Antidote against Drug-Induced Cardiotoxicity and Neurotoxicity: Focus on Nrf2 Pathway

et al. 2022

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Different drug classes such as antineoplastic drugs (anthracyclines, cyclophosphamide, 5-fluorouracil, taxanes, tyrosine kinase inhibitors), antiretroviral drugs, antipsychotic, and immunosuppressant drugs are known to induce cardiotoxic and neurotoxic effects. Recent studies have demonstrated that the impairment of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway is a primary event in the pathophysiology of drug-induced cardiotoxicity and neurotoxicity. The Nrf2 pathway regulates the expression of different genes whose products are involved in antioxidant and inflammatory responses and the detoxification of toxic species. Cardiotoxic drugs, such as the anthracycline doxorubicin, or neurotoxic drugs, such as paclitaxel, suppress or impair the Nrf2 pathway, whereas the rescue of this pathway counteracts both the oxidative stress and inflammation that are related to drug-induced cardiotoxicity and neurotoxicity. Therefore Nrf2 represents a novel pharmacological target to develop new antidotes in the field of clinical toxicology. Interestingly, carnosine (β-alanyl-l-histidine), an endogenous dipeptide that is characterized by strong antioxidant, anti-inflammatory, and neuroprotective properties is able to rescue/activate the Nrf2 pathway, as demonstrated by different preclinical studies and preliminary clinical evidence. Starting from these new data, in the present review, we examined the evidence on the therapeutic potential of carnosine as an endogenous antidote that is able to rescue the Nrf2 pathway and then counteract drug-induced cardiotoxicity and neurotoxicity.

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Hesperidin protects against cisplatin-induced cardiotoxicity in mice by regulating the p62–Keap1–Nrf2 pathway

Abstract: Hesperidin may be a potential strategy to inhibit oxidative stress-mediated inflammation and apoptosis by regulating the p62–Keap1–Nrf2 pathway in attenuating cardiotoxicity induced by cisplatin.

Cited by 12 publications

References 51 publications

Tannic acid alleviates ETEC K88‐induced intestinal damage through regulating the p62‐keap1‐Nrf2 and TLR4‐NF‐κB‐NLRP3 pathway in IPEC‐J2 cells

Tannic acid alleviates ETEC K88‐induced intestinal damage through regulating the p62‐keap1‐Nrf2 and TLR4‐NF‐κB‐NLRP3 pathway in IPEC‐J2 cells

The role of autophagy in cardiovascular disease: Cross-interference of signaling pathways and underlying therapeutic targets

The Therapeutic Potential of Carnosine as an Antidote against Drug-Induced Cardiotoxicity and Neurotoxicity: Focus on Nrf2 Pathway

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