PERK regulates Nrf2/ARE antioxidant pathway against dibutyl phthalate-induced mitochondrial damage and apoptosis dependent of reactive oxygen species in mouse spermatocyte-derived cells

Zhang, Guowei; Wang, Yang; Fan, Jun; Zou, Peng; Zeng, Yingfei; Liu, Xi; Zhou, Ziyuan; Cao, Jia; Ao, Lin

doi:10.1016/j.toxlet.2019.03.007

Cited by 41 publications

(13 citation statements)

References 34 publications

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“…Nuclear factor-E2-related factor 2 (Nrf2), a key transcription factor, can resist the development of oxidative damage in cells, influence the balance of redox metabolism and signaling, and promote the expression of a series of genes that confer protection against oxidative stress, such as NAD (P) H: quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1), glutamate-cysteine ligase regulatory subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC). The expression of these genes can reduce oxidative and inflammatory damage and enhance antioxidant capacity in the body [ 15 , 16 ]. Moreover, Nrf2 expression is also involved in the differentiation of Th2 cells and promotes the transcription of IL-10 in T cells [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

hPMSCs inhibit the expression of PD-1 in CD4+IL-10+ T cells and mitigate liver damage in a GVHD mouse model by regulating the crosstalk between Nrf2 and NF-κB signaling pathway

Zhang

et al. 2021

Stem Cell Res Ther

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Background The activation of T cells and imbalanced redox metabolism enhances the development of graft-versus-host disease (GVHD). Human placenta-derived mesenchymal stromal cells (hPMSCs) can improve GVHD through regulating T cell responses. However, whether hPMSCs balance the redox metabolism of CD4+IL-10+ T cells and liver tissue and alleviate GVHD remains unclear. This study aimed to investigate the effect of hPMSC-mediated treatment of GVHD associated with CD4+IL-10+ T cell generation via control of redox metabolism and PD-1 expression and whether the Nrf2 and NF-κB signaling pathways were both involved in the process. Methods A GVHD mouse model was induced using 6–8-week-old C57BL/6 and Balb/c mice, which were treated with hPMSCs. In order to observe whether hPMSCs affect the generation of CD4+IL-10+ T cells via control of redox metabolism and PD-1 expression, a CD4+IL-10+ T cell culture system was induced using human naive CD4+ T cells. The percentage of CD4+IL-10+ T cells and their PD-1 expression levels were determined in vivo and in vitro using flow cytometry, and Nrf2, HO-1, NQO1, GCLC, GCLM, and NF-κB levels were determined by western blotting, qRT-PCR, and immunofluorescence, respectively. Hematoxylin-eosin, Masson’s trichrome, and periodic acid-Schiff staining methods were employed to analyze the changes in hepatic tissue. Results A decreased activity of superoxide dismutase (SOD) and a proportion of CD4+IL-10+ T cells with increased PD-1 expression were observed in GVHD patients and the mouse model. Treatment with hPMSCs increased SOD activity and GCL and GSH levels in the GVHD mouse model. The percentage of CD4+IL-10+ T cells with decreased PD-1 expression, as well as Nrf2, HO-1, NQO1, GCLC, and GCLM levels, both in the GVHD mouse model and in the process of CD4+IL-10+ T cell generation, were also increased, but NF-κB phosphorylation and nuclear translocation were inhibited after treatment with hPMSCs, which was accompanied by improvement of hepatic histopathological changes. Conclusions The findings suggested that hPMSC-mediated redox metabolism balance and decreased PD-1 expression in CD4+IL-10+ T cells were achieved by controlling the crosstalk between Nrf2 and NF-κB, which further provided evidence for the application of hPMSC-mediated treatment of GVHD.

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Section: Introductionmentioning

confidence: 99%

hPMSCs inhibit the expression of PD-1 in CD4+IL-10+ T cells and mitigate liver damage in a GVHD mouse model by regulating the crosstalk between Nrf2 and NF-κB signaling pathway

Zhang

et al. 2021

Stem Cell Res Ther

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“…Previous studies have shown synergy between quercetin and kaempferol associated with antioxidant activity and Nrf2-ARE (Saw et al, 2014). The NRF2 pathway can further regulate mitochondrial damage by regulating ROS, thereby affecting mitochondrial apoptosis (Zhang et al, 2019). Studies have shown that kaempferol exerts a significant protective effect on cell mitochondrial disorders and the inhibition of ROS production, oxidative stress and mitochondria is the main mechanism of kaempferol protection in cells (Ondricek et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Supplementation of kaempferol toin vitromaturation medium regulates oxidative stress and enhances subsequent embryonic developmentin vitro

Zhao

et al. 2019

Zygote

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SummaryKaempferol (KAE) is one of the most common dietary flavonols possessing biological activities such as anticancer, anti-inflammatory and antioxidant effects. Although previous studies have reported the biological activity of KAE on a variety of cells, it is not clear whether KAE plays a similar role in oocyte and embryo in vitro culture systems. This study investigated the effect of KAE addition to in vitro maturation on the antioxidant capacity of embryos in porcine oocytes after parthenogenetic activation. The effects of kaempferol on oocyte quality in porcine oocytes were studied based on the expression of related genes, reactive oxygen species, glutathione and mitochondrial membrane potential as criteria. The rate of blastocyst formation was significantly higher in oocytes treated with 0.1 µm KAE than in control oocytes. The mRNA level of the apoptosis-related gene Caspase-3 was significantly lower in the blastocysts derived from KAE-treated oocytes than in the control group and the mRNA expression of the embryo development-related genes COX2 and SOX2 was significantly increased in the KAE-treated group compared with that in the control group. Furthermore, the level of intracellular reactive oxygen species was significantly decreased and that of glutathione was significantly increased after KAE treatment. Mitochondrial membrane potential (ΔΨm) was increased and the activity of Caspase-3 was significantly decreased in the KAE-treated group compared with that in the control group. Taken together, these results suggested that KAE is beneficial for the improvement of embryo development by inhibiting oxidative stress in porcine oocytes.

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“…Moreover, our data suggest that DFX treatment provoked a testis antioxidant response as evidenced by the upregulation of NRF2 and one of its targets, GPX4, the stability of which was shown to be associated with the ability of the latter to bind Bip [52]. It is difficult to ascertain whether this antioxidant response is secondary to the activation of the ER/UPR stress pathway PERK [53] or the result of DFXinduced oxidative stress. Since there was no evidence that the PERK/CHOP pathway was triggered, because neither PERK nor CHOP was upregulated in the DFX-treated testis samples, we made the assumption that we had observed DFX-associated oxidative stress.…”

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confidence: 82%

Deferasirox, an Iron‐Chelating Agent, Improves Testicular Morphometric and Sperm Functional Parameters in a Rat Model of Varicocele

Rahmani

Tavalaee

Hosseini

et al. 2021

Oxidative Medicine and Cellular Longevity

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Varicocele is characterized by testicular dysfunction that originates from hyperthermia and hypoxia, leading to defects in testicular tissue and altered spermatozoa structure and function. The varicocele testis is characterized by the presence of intracellular iron deposits that contribute to the associated oxidative stress. Therefore, we tested the hypothesis that administration of an iron-chelating agent, such as deferasirox (DFX), could potentially mitigate the consequences of varicocele on testicular tissue and spermatozoa. Using a well-established rat model of varicocele (VCL), we show that treatment with DFX partially improved the structure and function of the testis and spermatozoa. In particular, sperm motility was markedly restored whereas abnormal sperm morphology was only partially improved. No significant improvement in sperm count was observed that could be associated with the proapoptotic response observed following iron chelation treatment. No reduction in oxidative damage to spermatozoa was observed since lipid peroxidation and DNA integrity were not modified. This was suggested to be a result of increased oxidative stress. Finally, we also saw no indication of attenuation of the endoplasmic reticulum/unfolded protein (ER/UPR) stress response that we recently found associated with the VCL testis in rats.

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PERK regulates Nrf2/ARE antioxidant pathway against dibutyl phthalate-induced mitochondrial damage and apoptosis dependent of reactive oxygen species in mouse spermatocyte-derived cells

Cited by 41 publications

References 34 publications

hPMSCs inhibit the expression of PD-1 in CD4+IL-10+ T cells and mitigate liver damage in a GVHD mouse model by regulating the crosstalk between Nrf2 and NF-κB signaling pathway

hPMSCs inhibit the expression of PD-1 in CD4+IL-10+ T cells and mitigate liver damage in a GVHD mouse model by regulating the crosstalk between Nrf2 and NF-κB signaling pathway

Supplementation of kaempferol toin vitromaturation medium regulates oxidative stress and enhances subsequent embryonic developmentin vitro

Deferasirox, an Iron‐Chelating Agent, Improves Testicular Morphometric and Sperm Functional Parameters in a Rat Model of Varicocele

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