Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats

Gl, Hong; Qq, Cai; Jp, Tan; Xz, Jiang; Gj, Zhao; Wu, Biao; Mf, Li; Qm, Qiu; Zq, Lu

doi:10.1177/0960327114532381

Cited by 13 publications

(10 citation statements)

References 33 publications

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“…On an other hand it has been reported that glioblastoma is characterized by aberrant activation of inflammatory responses; von Wedel-Parlow et al, reported that the pro-inflammatory cytokines interleukin-1 (IL-1b) and tumor necrosis factor-a (TNF-alpha) affect the expression of cerebral ABC-transporters in primary endothelial cells, the anti-inflammatory glucocorticoid hydrocortisone leads to a induction of Abcg2 (BCRP) and Abcc1 (MRP) mRNA in microvascular endothelial cells whereas Abcb1 (P-gp)gene expression is down-regulated ( 49 ). It has been reported that mifepristone decreased the levels of of TNF-alpha in rats exposed to Paraquat ( 50 ), and in endometrial epithelial and stromal cells reduced the secretion of IL-6 and TNF-alpha ( 51 ). However, more research is necessary to better understand the regulation and the role of mifepristone in efflux pump transporters.…”

Section: Discussionmentioning

confidence: 99%

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

et al. 2020

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Glioblastoma, the most common primary central nervous system tumor, is characterized by extensive vascular neoformation and an area of necrosis generated by rapid proliferation. The standard treatment for this type of tumor is surgery followed by chemotherapy based on temozolomide and radiotherapy, resulting in poor patient survival. Glioblastoma is known for strong resistance to treatment, frequent recurrence and rapid progression. The aim of this study was to evaluate whether mifepristone, an antihormonal agent, can enhance the effect of temozolomide on C6 glioma cells orthotopically implanted in Wistar rats. The levels of the vascular endothelial growth factor (VEGF), and P-glycoprotein (P-gp) were examined, the former a promoter of angiogenesis that facilitates proliferation, and the latter an efflux pump transporter linked to drug resistance. After a 3-week treatment, the mifepristone/temozolomide regimen had decreased the level of VEGF and P-gp and significantly reduced tumor proliferation (detected by PET/CT images based on 18F-fluorothymidine uptake). Additionally, mifepristone proved to increase the intracerebral concentration of temozolomide. The lower level of O6-methylguanine-DNA-methyltransferase (MGMT) (related to DNA repair in tumors) previously reported for this combined treatment was herein confirmed. After the mifepristone/temozolomide treatment ended, however, the values of VEGF, P-gp, and MGMT increased and reached control levels by 14 weeks post-treatment. There was also tumor recurrence, as occurred when administering temozolomide alone. On the other hand, temozolomide led to 100% mortality within 26 days after beginning the drug treatment, while mifepristone/temozolomide enabled 70% survival 60–70 days and 30% survived over 100 days, suggesting that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide.

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Section: Discussionmentioning

confidence: 99%

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

et al. 2020

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“…The current study demonstrated increased SIRT1 expression levels in mouse lung tissue at 6 and 24 h after PQ A major mechanism in the cellular defense against oxidative stress is the activation of the NRF2 antioxidant response element signaling pathway (20). Previous studies have demonstrated that NRF2 is important in PQ-induced lung injury; PQ can inhibit the NRF2 expression in vitro and in vivo (6,21). Additionally, overexpression of NRF2 can ameliorate PQ-induced lung injury and cell apoptosis (21,22).…”

Section: Discussionmentioning

confidence: 54%

“…SIRT1 regulates a wide variety of cellular processes by deacetylating histones and numerous other crucial transcription factors, including factors in control of ROS production (5). The nuclear factor, erythroid 2-like 2 (NRF2) transcription factor is a member of the cap 'n' collar basic-region leucine zipper transcription factors, and is considered an effective target for antioxidant therapy for PQ poisoning (3,6). Previous studies have demonstrated that the SIRT1-mediated deacetylation of NRF2 terminated the transcription of antioxidant genes (7).…”

Section: Introductionmentioning

confidence: 99%

Resveratrol protects mice from paraquat-induced lung injury: The important role of SIRT1 and NRF2 antioxidant pathways

Zhao

Chen

et al. 2015

Molecular Medicine Reports

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Abstract. Sirtuin 1 (SIRT1) acts via the deacetylation of a number of crucial transcription factors and has been implicated in various biological processes, including oxidative stress. Previous studies have indicated that nuclear factor, erythroid 2-like 2 (NRF2) is an effective target of antioxidant therapy for paraquat (PQ) poisoning. However, the association between SIRT1 and NRF2 and their effects in PQ-induced oxidative stress remains to be elucidated. The current study demonstrated that PQ exposure upregulated the expression of SIRT1 and NRF2 following 6-and 24-h exposure in the lungs of mice. However, long-term exposure to PQ significantly decreased the expression of SIRT1 and NRF2. Resveratrol is a SIRT1 activator, and strongly enhanced SIRT1 expression and attenuated the lung injury resulting from PQ exposure in the current study. Additionally, treatment with resveratrol upregulated the expression of NRF2 and glutathione, increased the activity of heme oxygenase-1, superoxide dismutase and catalase, but depleted the expression of malondialdehyde. The present results demonstrated that resveratrol reduced PQ-induced oxidative stress and lung injury, potentially through the positive feedback signaling loop between SIRT1 and NRF2.

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“…Nuclear factor E2-related factor 2 (NRF2) is an important transcription factor, which regulates genes associated with the scavenging of oxygen free radicals, and is regarded as an effective target for antioxidant therapy (9,10). Under conditions of oxidative stress, NRF2 translocates to the nucleus, and then induces the gene expression of downstream detoxification enzymes and antioxidant enzymes, such as superoxide dismutase (SOD) and heme oxygenase-1 (HO-1), in order to produce an antioxidant effect (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

SIRT1 exerts protective effects against paraquat-induced injury in mouse type II alveolar epithelial cells by deacetylating NRF2 in vitro

Ding

Zhao

et al. 2016

International Journal of Molecular Medicine

118

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Silent information regulator 2-related enzyme 1 (SIRT1), a protein deacetylase, is known to strongly protect cells against oxidative stress-induced injury. The nuclear factor E2-related factor 2 (NRF2)-antioxidant response element (ARE) antioxidant pathway plays important regulatory roles in the antioxidant therapy of paraquat (PQ) poisoning. In the present study, we investigated whether the SIRT1/NRF2/ARE signaling pathway plays an important role in lung injury induced by PQ. For this purpose, mouse type II alveolar epithelial cells (AECs‑II) were exposed to various concentrations of PQ. The overexpression or silencing of SIRT1 was induced by transfecting the cells with a SIRT1 overexpression vector or shRNA targeting SIRT1, respectively. The protein expression levels of SIRT1 and NRF2 were measured by western blot analysis. The superoxide dismutase (SOD) and catalase (CAT) activities, as well as the glutathione (GSH) and malondialdehyde (MDA) levels were measured using respective kits. Heme oxygenase-1 (HO-1) activity was also determined by ELISA. In addition, cell apoptosis was determined by flow cytometry. The protein stability of NRF2 was analyzed using cycloheximide and its acetylation in the cells was also determined. The following findings were obtained: i) SIRT1 overexpression markedly increased NRF2 protein expression; ii) SIRT1 promoted the transcriptional activity of NRF2 and upregulated the expression of the NRF2 downstream genes, SOD, CAT, GSH and HO-1, thus inhibiting the apoptosis of AECs‑II; iii) the inhibition of SIRT1 activity further induced the production of malondialdehyde (MDA), which resulted in increased oxidative damage; iv) SIRT1 promoted the stability of NRF2 by regulating the deacetylation and activation of the NRF2/ARE antioxidant pathway. The findings of this study demonstrate that the protective effects of SIRT1 are associated with the activation of the NRF2/ARE antioxidant pathway in lung injury induced by PQ poisoning.

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Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats

Cited by 13 publications

References 33 publications

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

Resveratrol protects mice from paraquat-induced lung injury: The important role of SIRT1 and NRF2 antioxidant pathways

SIRT1 exerts protective effects against paraquat-induced injury in mouse type II alveolar epithelial cells by deacetylating NRF2 in vitro

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