Modulation of NRF2/ARE pathway- and cell death-related genes during drug-induced liver injury

Ghanim, Bayan Y.; Ahmad, Mohammad I.; Abdallah, Qasem; Qatouseh, Luay Abu; Qinna, Nidal A.

doi:10.1177/09603271211027947

Cited by 13 publications

(2 citation statements)

References 49 publications

(54 reference statements)

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“…This is consistent with reports that Nrf2 activation does not necessarily alter the expression of all its target genes. There exists a complex network of other transcriptional factors whose cellular signaling may regulate the activation of different subsets of genes [ 45 ]. While we propose that carvedilol pretreatment reduces cellular oxidants and nuclear Nrf2 localization, our gene expression analysis reveals that DOX treatment results in the activation of the antioxidant response, whether or not there was prior treatment with carvedilol.…”

Section: Resultsmentioning

confidence: 99%

Carvedilol Phenocopies PGC-1α Overexpression to Alleviate Oxidative Stress, Mitochondrial Dysfunction and Prevent Doxorubicin-Induced Toxicity in Human iPSC-Derived Cardiomyocytes

Uche,

Dai,

Lai

et al. 2023

Antioxidants

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Doxorubicin (DOX), one of the most effective and widely used anticancer drugs, has the major limitation of cancer treatment-related cardiotoxicity (CTRTOX) in the clinic. Reactive oxygen species (ROS) generation and mitochondrial dysfunction are well-known consequences of DOX-induced injury to cardiomyocytes. This study aimed to explore the mitochondrial functional consequences and associated mechanisms of pretreatment with carvedilol, a ß-blocking agent known to exert protection against DOX toxicity. When disease modeling was performed using cultured rat cardiac muscle cells (H9c2 cells) and human iPSC-derived cardiomyocytes (iPSC-CMs), we found that prophylactic carvedilol mitigated not only the DOX-induced suppression of mitochondrial function but that the mitochondrial functional readout of carvedilol-pretreated cells mimicked the readout of cells overexpressing the major regulator of mitochondrial biogenesis, PGC-1α. Carvedilol pretreatment reduces mitochondrial oxidants, decreases cell death in both H9c2 cells and human iPSC-CM and maintains the cellular ‘redox poise’ as determined by sustained expression of the redox sensor Keap1 and prevention of DOX-induced Nrf2 nuclear translocation. These results indicate that, in addition to the already known ROS-scavenging effects, carvedilol has a hitherto unrecognized pro-reducing property against the oxidizing conditions induced by DOX treatment, the sequalae of DOX-induced mitochondrial dysfunction and compromised cell viability. The novel findings of our preclinical studies suggest future trial design of carvedilol prophylaxis, such as prescreening for redox state, might be an alternative strategy for preventing oxidative stress writ large in lieu of the current lack of clinical evidence for ROS-scavenging agents.

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Section: Resultsmentioning

confidence: 99%

Carvedilol Phenocopies PGC-1α Overexpression to Alleviate Oxidative Stress, Mitochondrial Dysfunction and Prevent Doxorubicin-Induced Toxicity in Human iPSC-Derived Cardiomyocytes

Uche,

Dai,

Lai

et al. 2023

Antioxidants

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“…Although a decrease in Nrf2 gene expression was observed, our Western blot results show its post-translational activation. Once uncoupled from Keap1, Nrf2 translocates to the nucleus where it heterodimerizes with sMaf proteins and binds to electrophilic response gene (EpRE) motifs that encode detoxifying enzymes (e.g., Nqo1), antioxidant enzymes (e.g., Sod2, Cat), heme detoxifying enzymes (e.g., Hmox1) and enzymes involved in GSH synthesis (e.g., Gclc) [93,94].…”

Section: Discussionmentioning

confidence: 99%

Molecular and Antioxidant Characterization of Opuntia robusta Fruit Extract and Its Protective Effect against Diclofenac-Induced Acute Liver Injury in an In Vivo Rat Model

et al. 2023

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A molecular characterization of the main phytochemicals and antioxidant activity of Opuntia robusta (OR) fruit extract was carried out, as well as an evaluation of its hepatoprotective effect against diclofenac (DF)-induced acute liver injury. Phenols, flavonoids and betalains were quantified, and antioxidant characterization was performed by means of the ABTS•+, DPPH and FRAP assays. The identification of the main biocompounds present in OR fruit extract was carried out via UPLC-QTOF-MS/MS. In the in vivo model, groups of rats were treated prophylactically with the OR fruit extract, betanin and N-acteylcysteine followed by a single dose of DF. Biochemical markers of oxidative stress (MDA and GSH) and relative gene expression of the inducible antioxidant response (Nrf2, Sod2, Hmox1, Nqo1 and Gclc), cell death (Casp3) and DNA repair (Gadd45a) were analyzed. Western blot analysis was performed to measure protein levels of Nrf2 and immunohistochemical analysis was used to assess caspase-3 activity in the experimental groups. Our results demonstrate that the OR fruit extract showed strong antioxidant and cytoprotective capacity due to the presence of bioactive compounds, such as betalain and phenols. We conclude that OR fruit extract or selected components can be used clinically to support patients with acute liver injury.

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Absence of IκBβ/NFκB signaling does not attenuate acetaminophen‐induced hepatic injury

Solar

Grayck

McCarthy

et al. 2022

The Anatomical Record

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Acetaminophen (N‐acetyl‐p‐aminophenol [APAP]) toxicity is a common cause of acute liver failure. Innate immune signaling and specifically NFκB activation play a complex role in mediating the hepatic response to toxic APAP exposures. While inflammatory innate immune responses contribute to APAP‐induced injury, these same pathways play a role in regeneration and repair. Previous studies have shown that attenuating IκBβ/NFκB signaling downstream of TLR4 activation can limit injury, but whether this pathway contributes to APAP‐induced hepatic injury is unknown. We hypothesized that the absence of IκBβ/NFκB signaling in the setting of toxic APAP exposure would attenuate APAP‐induced hepatic injury. To test this, we exposed adult male WT and IκBβ−/− mice to APAP (280 mg/kg, IP) and evaluated liver histology at early (2–24 hr) and late (48–72 hr) time points. Furthermore, we interrogated the hepatic expression of NFκB inflammatory (Cxcl1, Tnf, Il1b, Il6, Ptgs2, and Ccl2), anti‐inflammatory (Il10, Tnfaip3, and Nfkbia), and Nrf2/antioxidant (Gclc, Hmox, and Nqo1) target genes previously demonstrated to play a role in APAP‐induced injury. Conflicting with our hypothesis, we found that hepatic injury was similar in WT and IκBβ−/− mice. Acutely, the induced expression of some target genes was similar in WT and IκBβ−/− mice (Tnfaip3, Nfkbia, and Gclc), while others were either not induced (Cxcl1, Tnf, Ptgs2, and Il10) or significantly attenuated (Ccl2) in IκBβ−/− mice. At later time points, APAP‐induced hepatic expression of Il1b, Il6, and Gclc was significantly attenuated in IκBβ−/− mice. Based on these findings, the therapeutic potential of targeting IκBβ/NFκB signaling to treat toxic APAP‐induced hepatic injury is likely limited.

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Modulation of NRF2/ARE pathway- and cell death-related genes during drug-induced liver injury

Cited by 13 publications

References 49 publications

Carvedilol Phenocopies PGC-1α Overexpression to Alleviate Oxidative Stress, Mitochondrial Dysfunction and Prevent Doxorubicin-Induced Toxicity in Human iPSC-Derived Cardiomyocytes

Carvedilol Phenocopies PGC-1α Overexpression to Alleviate Oxidative Stress, Mitochondrial Dysfunction and Prevent Doxorubicin-Induced Toxicity in Human iPSC-Derived Cardiomyocytes

Molecular and Antioxidant Characterization of Opuntia robusta Fruit Extract and Its Protective Effect against Diclofenac-Induced Acute Liver Injury in an In Vivo Rat Model

Absence of IκBβ/NFκB signaling does not attenuate acetaminophen‐induced hepatic injury

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