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?-Lipoic acid prevents against cisplatin cytotoxicity via activation of the NRF2/HO-1 antioxidant pathway.

ABSTRACT: The production of reactive oxygen species (ROS) by cisplatin is one of the major mechanisms of cisplatin-induced cytotoxicity. We examined the preventive effect of ?-lipoic acid (LA) on cisplatin-induced toxicity via its antioxidant effects on in vitro and ex vivo culture systems. To elucidate the mechanism of the antioxidant activity of LA, NRF2 was inhibited using NRF2 siRNA, and the change in antioxidant activity of LA was characterized. MTT assays showed that LA was safe at concentrations up to 0.5 mM in HEI-OC1 cells and had a protective effect against cisplatin-induced cytotoxicity. Intracellular ROS production in HEI-OC1 cells was rapidly increased by cisplatin for up to 48 h. However, treatment with LA significantly reduced the production of ROS and increased the expression of the antioxidant proteins HO-1 and SOD1. Ex vivo, the organs of Corti of the group pretreated with LA exhibited better preservation than the group that received cisplatin alone. We also confirmed the nuclear translocation of NRF2 after LA administration, and that NRF2 inhibition decreased the antioxidant activity of LA. Together, these results indicate that the antioxidant activity of LA was through the activation of the NRF2/HO-1 antioxidant pathway.

SUBMITTER: Lee J

PROVIDER: S-EPMC6932784 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation.

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Anti-allergic rhinitis activity of α-lipoic acid via balancing Th17/Treg expression and enhancing Nrf2/HO-1 pathway signaling.

Project description:An ovalbumin (OVA)-induced allergic rhinitis (AR) mouse model was established to investigate whether α-Lipoic acid (LA) has a protective effect against upper respiratory tract inflammation. BALB/c mice were sensitized by intraperitoneal injection and challenged by intranasal application of OVA. Mice were orally administered various doses of LA once daily (2, 10, 50 mg/kg) and dexamethasone (Dex; 2.5 mg/kg) 1 h before OVA challenge. Allergic nasal symptoms, levels of OVA-specific immunoglobulins, cytokines, and transcription factors were measured. Nasal and lung histopathology were evaluated. LA administration significantly alleviated the nasal symptoms such as rubbing and sneezing, markedly reduced both serum OVA-specific IgE and IgG1 levels. The LA treatment group showed markedly up-regulated levels of the Treg cytokine IL-10 and Treg transcription factor Foxp3. In contrast, it showed down-regulated levels of the Th17 cytokine IL-17 and the Th17 transcription factor STAT3, and RORγ. LA greatly enhanced the nuclear factor erythroid-derived 2/heme oxygenase 1 (Nrf2/HO-1) pathway signaling and inhibited the activation of NF-κB/IκB, markedly suppressed the levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, IL-8 and chemokine COX-2. The histologic alterations of nasal and lung tissues of AR mice were effectively ameliorated by LA. Based on these results, we suggest that LA could be a potential therapeutic agent in OVA-induced AR by virtue of its role in controlling the Th17/Treg balance and enhancing Nrf2/HO-1 pathway signaling.

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Polydatin activates the Nrf2/HO-1 signaling pathway to protect cisplatin-induced hearing loss in guinea pigs.

Project description:Irreversible sensorineural hearing loss is one of the most common side effects after cisplatin treatment. Prevention and reversal of hearing loss caused by cisplatin are of great importance for cancer patients, especially children. Oxidative stress is an important cause of hearing loss resulted from cisplatin, unfortunately, there is no drug yet available that can completely prevent and reverse the ototoxicity from cisplatin. Polydatin (PD) possesses excellent antioxidant and anti-inflammatory effects, however, its role in the cisplatin-induced hearing loss has not been investigated. Herein, we have explored the preventive and therapeutic effects of PD on cisplatin-induced hearing loss and the possible underlying mechanisms. In the in vivo setting with guinea pigs, we have demonstrated that PD can reduce the threshold shift of auditory brainstem response (ABR) caused by cisplatin, promote the nuclear translocation of Nuclear factor erythroid-2 related factor 2 (Nrf2), increase the expression of Nrf2 and heme oxygenase-1 (HO-1), and thus reduce the loss of outer hair cells (OHCs). PD can ameliorate cisplatin-induced hearing loss through activating the Nrf2/HO-1 signaling pathway. This study provides a potential strategy for preventing and improving hearing loss resulted from cisplatin treatment in clinics.

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Zinc Finger Protein 90 Knockdown Promotes Cisplatin Sensitivity via Nrf2/HO-1 Pathway in Ovarian Cancer Cell.

Project description:Our study discussed the role of Zfp90 in ovarian cancer (OC) cell lines' sensitivity to cisplatin. We used two OC cell lines, SK-OV-3 and ES-2, to evaluate their role in cisplatin sensitization. The protein levels of p-Akt, ERK, caspase 3, Bcl-2, Bax, E-cadherin, MMP-2, MMP-9 and other drug resistance-related molecules, including Nrf2/HO-1, were discovered in the SK-OV-3 and ES-2 cells. We also used a human ovarian surface epithelial cell to compare the effect of Zfp90. Our outcomes indicated that cisplatin treatment generates reactive oxygen species (ROS) that modulate apoptotic protein expression. The anti-oxidative signal was also stimulated, which could hinder cell migration. The intervention of Zfp90 could greatly improve the apoptosis pathway and block the migrative pathway to regulate the cisplatin sensitivity in the OC cells. This study implies that the loss of function of Zfp90 might promote cisplatin sensitization in OC cells via regulating the Nrf2/HO-1 pathway to enhance cell apoptosis and inhibit the migrative effect in both SK-OV-3 and ES-2 cells.

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Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway.

Project description:The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents.

| S-EPMC3314920 | biostudies-literature

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