Hepatic hypoxia-inducible factors inhibit PPARα expression to exacerbate acetaminophen induced oxidative stress and hepatotoxicity

Li, Dawei; Du, Yingdong; Yuan, Xiaodong; Han, Xiaoxiao; Dong, Zhong; Chen, Xiaosong; Wu, Haoyu; Zhang, Jianjun; Xu, Leilei; Han, Conghui; Zhang, Ming; Xia, Qiang

doi:10.1016/j.freeradbiomed.2017.06.002

Cited by 35 publications

(28 citation statements)

References 46 publications

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“…On the other hand, administration of APAP to mice induces malondialdehyde and myeloperoxidase formation and decreases in hepatic levels of SOD and glutathione, which aggravates oxidative damage to further lead to liver tissue damage ( Wu et al, 2017 ). To date, the consensus of opinion is that the metabolite of APAP results in depletion of GSH and formation of GSSG that contributes to cause mitochondrial oxidant stress and ultimately promote liver injury ( Li et al, 2017 ). In addition, previous abundant researches indicated that APAP-induced hepatic structural integrity by displaying serious destruction of hepatic architecture, necrosis, and infiltration of inflammatory cells ( Hasanein and Sharifi, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity

Xiao

Zhou

et al. 2018

Front. Pharmacol.

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Acetaminophen (APAP) overdose-induced fatal hepatotoxicity is majorly characterized by overwhelmingly increased oxidative stress while enhanced nuclear factor-erythroid 2-related factor 2 (Nrf2) is involved in prevention of hepatotoxicity. Although Licochalcone A (Lico A) upregulates Nrf2 signaling pathway against oxidative stress-triggered cell injury, whether it could protect from APAP-induced hepatotoxicity by directly inducing Nrf2 activation is still poorly elucidated. This study aims to explore the protective effect of Lico A against APAP-induced hepatotoxicity and its underlying molecular mechanisms. Our findings indicated that Lico A effectively decreased tert-butyl hydroperoxide (t-BHP)- and APAP-stimulated cell apoptosis, mitochondrial dysfunction and reactive oxygen species generation and increased various anti-oxidative enzymes expression, which is largely dependent on upregulating Nrf2 nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element promoter activity. Meanwhile, Lico A dramatically protected against APAP-induced acute liver failure by lessening the lethality; alleviating histopathological liver changes; decreasing the alanine transaminase and aspartate aminotransferase levels, malondialdehyde formation, myeloperoxidase level and superoxide dismutase depletion, and increasing the GSH-to-GSSG ratio. Furthermore, Lico A not only significantly modulated apoptosis-related protein by increasing Bcl-2 expression, and decreasing Bax and caspase-3 cleavage expression, but also efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, inhibiting Bax mitochondrial translocation, apoptosis-inducing factor and cytochrome c release. However, Lico A-inhibited APAP-induced the lethality, histopathological changes, hepatic apoptosis, and mitochondrial dysfunction in WT mice were evidently abrogated in Nrf2-/- mice. These investigations firstly implicated that Lico A has protective potential against APAP-induced hepatotoxicity which may be strongly associated with the Nrf2-mediated defense mechanisms.

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Section: Discussionmentioning

confidence: 99%

Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity

Xiao

Zhou

et al. 2018

Front. Pharmacol.

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“…We do not have an explanation for the differential rescuing action of 2-ME on the expression of the three CYP isoforms studied. We propose that hypoxia induces HIF-1α-dependent transcriptional repression of CYP2B6, CYP3A4 and CYP3A5; however, our results do not discard additional HIF-1α-independent regulatory mechanisms, including the activation of transcriptional repressors such as the small heterodimer partner (SHP), which has been implicated in the inhibition of the CYP7A1 isoform under hypoxic conditions, and the downregulation of nuclear receptors implicated in the positive regulation of CYP2B6, CYP3A4 and CYP3A5, namely PPARα, PPARγ or ER-α, as well as the constitutive androstane and pregnane X receptors, whose mRNA was found to be reduced by hypoxia (1% O 2 , 24 h) in hepatic HepaRG stem cells ( 21 , 51 , 52 , 63 – 65 ) In addition, post-transcriptional regulation of CYP expression implicates the action of diverse mRNA stabilizing molecules, microRNAs and long noncoding RNAs ( 66 ). Finally, 2-ME itself could act as a chemical modulator of CYP expression, because CYP substrates or their metabolites are capable of inducing CYP expression ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia increases chemoresistance in human medulloblastoma DAOY cells via hypoxia‑inducible factor 1α‑mediated downregulation of the CYP2B6, CYP3A4 and CYP3A5 enzymes and inhibition of cell proliferation

et al. 2018

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Medulloblastomas are among the most frequently diagnosed pediatric solid tumors, and drug resistance remains as the principal cause of treatment failure. Hypoxia and the subsequent activation of hypoxia-inducible factor 1α (HIF-1α) are considered key factors in modulating drug antitumor effectiveness, but the underlying mechanisms in medulloblastomas have not yet been clearly understood. The aim of the present study was to determine whether hypoxia induces resistance to cyclophosphamide (CPA) and ifosfamide (IFA) in DAOY medulloblastoma cells, whether the mechanism is dependent on HIF-1α, and whether involves the modulation of the expression of cytochromes P450 (CYP)2B6, 3A4 and 3A5 and the control of cell proliferation. Monolayer cultures of DAOY medulloblastoma cells were exposed for 24 h to moderate (1% O2) or severe (0.1% O2) hypoxia, and protein expression was evaluated by immunoblotting. Cytotoxicity was studied with the MTT assay and by Annexin V/PI staining and flow cytometry. Cell proliferation was determined by the trypan-blue exclusion assay and cell cycle by propidium iodide staining and flow cytometry. Hypoxia decreased CPA and IFA cytotoxicity in medulloblastoma cells, which correlated with a reduction in the protein levels of CYP2B6, CYP3A4 and CYP3A5 and inhibition of cell proliferation. These responses were dependent on hypoxia-induced HIF-1α activation, as evidenced by chemical inhibition of its transcriptional activity with 2-methoxyestradiol (2-ME), which enhanced the cytotoxic activity of CPA and IFA and increased apoptosis. Our results indicate that by stimulating HIF-1α activity, hypoxia downregulates the expression of CYP2B6, CYP3A4 and CYP3A5, that in turn leads to decreased conversion of CPA and IFA into their active forms and thus to diminished cytotoxicity. These results support that the combination of HIF-1α inhibitors and canonical antineoplastic agents provides a potential therapeutic alternative against medulloblastoma.

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“…Previous studies have shown that HIF-1α protein synthesis was regulated through the PI3K/AKT and MAPK pathways, and its expression is regarded as the suppression factor for HIF-1 DNA binding and transcriptional activities in many cultured cells ( Frede et al, 2006 ; Olson and van der Vliet, 2011 ; Yu et al, 2012 ). Another studies also demonstrated that HIF-1α contributes to the development of myeloid cell–mediated inflammation, facilitates the phagocytic function of macrophages and exacerbates the acetaminophen-induced oxidative stress and hepatotoxicity ( Cramer et al, 2003 ; Peyssonnaux et al, 2005 ; Li et al, 2017 ). Recently, HIF-1α was demonstrated to be increased in the lungs of COPD patients and activation of HIF-1α signaling pathway by cigarette smoke (CS), a key pathological driver of COPD, accelerates the development of COPD ( Ding et al, 2015 ; Baz-Davila et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Sodium Tanshinone IIA Sulfonate Decreases Cigarette Smoke-Induced Inflammation and Oxidative Stress via Blocking the Activation of MAPK/HIF-1α Signaling Pathway

Guan

Wang

et al. 2018

Front. Pharmacol.

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Aberrant activation of hypoxia-inducible factor (HIF)-1α is frequently encountered and promotes oxidative stress and inflammation in chronic obstructive pulmonary disease (COPD). The present study investigated whether sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, can mediate its effect through inhibiting HIF-1α–induced oxidative stress and inflammation in cigarette smoke (CS)-induced COPD in mice. Here, we found that STS improved pulmonary function, ameliorated emphysema and decreased the infiltration of inflammatory cells in the lungs of CS-exposed mice. STS reduced CS- and cigarette smoke extract (CSE)-induced upregulation of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the lungs and macrophages. STS also inhibited CSE-induced reactive oxygen species (ROS) production, as well as the upregulation of heme oxygenase (HO)-1, NOX1 and matrix metalloproteinase (MMP)-9 in macrophages. In addition, STS suppressed HIF-1α expression in vivo and in vitro, and pretreatment with HIF-1α siRNA reduced CSE-induced elevation of TNF-α, IL-1β, and HO-1 content in the macrophages. Moreover, we found that STS inhibited CSE-induced the phosphorylation of ERK, p38 MAPK and JNK in macrophages, and inhibition of these signaling molecules significantly repressed CSE-induced HIF-1α expression. It indicated that STS inhibits CSE-induced HIF-1α expression likely by blocking MAPK signaling. Furthermore, STS also promoted HIF-1α protein degradation in CSE-stimulated macrophages. Taken together, these results suggest that STS prevents COPD development possibly through the inhibition of HIF-1α signaling, and may be a novel strategy for the treatment of COPD.

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Hepatic hypoxia-inducible factors inhibit PPARα expression to exacerbate acetaminophen induced oxidative stress and hepatotoxicity

Cited by 35 publications

References 46 publications

Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity

Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity

Hypoxia increases chemoresistance in human medulloblastoma DAOY cells via hypoxia‑inducible factor 1α‑mediated downregulation of the CYP2B6, CYP3A4 and CYP3A5 enzymes and inhibition of cell proliferation

Sodium Tanshinone IIA Sulfonate Decreases Cigarette Smoke-Induced Inflammation and Oxidative Stress via Blocking the Activation of MAPK/HIF-1α Signaling Pathway

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